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BackgroundPlatelet transfusion carries risk of transfusion-transmitted infection (TTI). Pathogen reduction of platelet components (PRPC) is designed to reduce TTI. Pulmonary adverse events (AEs), including transfusion-related acute lung injury and acute respiratory distress syndrome (ARDS) occur with platelet transfusion.Study designAn open label, sequential cohort study of transfusion-dependent hematology-oncology patients was conducted to compare pulmonary safety of PRPC with conventional PC (CPC). The primary outcome was the incidence of treatment-emergent assisted mechanical ventilation (TEAMV) by non-inferiority. Secondary outcomes included: time to TEAMV, ARDS, pulmonary AEs, peri-transfusion AE, hemorrhagic AE, transfusion reactions (TRs), PC and red blood cell (RBC) use, and mortality.ResultsBy modified intent-to-treat (mITT), 1068 patients received 5277 PRPC and 1223 patients received 5487 CPC. The cohorts had similar demographics, primary disease, and primary therapy. PRPC were non-inferior to CPC for TEAMV (treatment difference -1.7%, 95% CI: (-3.3% to -0.1%); odds ratio=0.53, 95% CI: (0.30, 0.94). The cumulative incidence of TEAMV for PRPC (2.9%) was significantly less than CPC (4.6%, p= .039). The incidence of ARDS was less, but not significantly different, for PRPC (1.0% vs. 1.8%, p= .151; odds ratio=0.57, 95% CI: (0.27, 1.18). AE, pulmonary AE, and mortality were not different between cohorts. TRs were similar for PRPC and CPC (8.3% vs. 9.7%, p= .256); and allergic TR were significantly less with PRPC (p= .006). PC and RBC use were not increased with PRPC.DiscussionPRPC demonstrated reduced TEAMV with no excess treatment-related pulmonary morbidity.

PDF file - 522K, Percentage of CD8+T cells recognizing MUC1 tetramer in HLA 2.1+ patients.

Purpose: A multiple myeloma vaccine has been developed whereby patient-derived tumor cells are fused with autologous dendritic cells, creating a hybridoma that stimulates a broad antitumor response. We report on the results of a phase II trial in which patients underwent vaccination following autologous stem cell transplantation (ASCT) to target minimal residual disease.Experimental Design: Twenty-four patients received serial vaccinations with dendritic cell/myeloma fusion cells following posttransplant hematopoietic recovery. A second cohort of 12 patients received a pretransplant vaccine followed by posttransplant vaccinations. Dendritic cells generated from adherent mononuclear cells cultured with granulocyte macrophage colony-stimulating factor, interleukin-4, and TNF-α were fused with autologous bone marrow–derived myeloma fusion cells using polyethylene glycol. Fusion cells were quantified by determining the percentage of cells that coexpress dendritic cell and myeloma fusion antigens.Results: The posttransplant period was associated with reduction in general measures of cellular immunity; however, an increase in CD4 and CD8+ myeloma-specific T cells was observed after ASCT that was significantly expanded following posttransplant vaccination. Seventy-eight percent of patients achieved a best response of complete response (CR)+very good partial response (VGPR) and 47% achieved a CR/near CR (nCR). Remarkably, 24% of patients who achieved a partial response following transplant were converted to CR/nCR after vaccination and at more than 3 months posttransplant, consistent with a vaccine-mediated effect on residual disease.Conclusions: The posttransplant period for patients with multiple myeloma provides a unique platform for cellular immunotherapy in which vaccination with dendritic cell/myeloma fusion fusions resulted in the marked expansion of myeloma-specific T cells and cytoreduction of minimal residual disease. Clin Cancer Res; 19(13); 3640–8. ©2013 AACR.

Context.— Substantial variability between different antibody titration methods has been identified since the development and introduction of the uniform procedure in 2008. Objective.— To determine whether more recent methods or techniques decrease interlaboratory and intralaboratory variation measured using proficiency testing. Design.— Proficiency test data for antibody titration between 2014 and 2018 were obtained from the College of American Pathologists. Interlaboratory and intralaboratory variations were compared by analyzing the distribution of titer results by method and phase, comparing the results against the supplier's quality control titer, and by evaluating the distribution of paired titer results when each laboratory received a sample with the same titer twice. Results.— A total of 1337 laboratories participated in the antibody titer proficiency test during the study period. Only 54.1% (5874 of 10 852) of anti-D and 63.4% (3603 of 5680) of anti-A reported responses were within 1 titer of the supplier's intended result. Review of the agreement between laboratories of the same methodology found 78.4% (3139 of 4004) for anti-A and 89.0% (9655 of 10 852) of laboratory responses for anti-D fell within 1 titer of the mode response. When provided with 2 consecutive samples of the same titer (anti-D titer: 16), 85% (367 of 434) of laboratories using the uniform procedure and 80% (458 of 576) using the other method reported a titer difference of 1 or less. Conclusions.— Despite advances, interlaboratory and intralaboratory variance for this assay remains high in comparison with the strong reliance on titer results in clinical practice. There needs to be a reevaluation of the role of this test in clinical decision-making.

Accumulating evidence from clinical trials suggests that a lower (restrictive) hemoglobin threshold (8% g/dL) for red blood cell (RBC) transfusion, compared with a higher (liberal) threshold (≥10 g/dL) is safe. However, in anemic patients with acute myocardial infarction (MI), maintaining a higher hemoglobin level may increase oxygen delivery to vulnerable myocardium resulting in improved clinical outcomes. Conversely, RBC transfusion may result in increased blood viscosity, vascular inflammation, and reduction in available nitric oxide resulting in worse clinical outcomes. We hypothesize that a liberal transfusion strategy would improve clinical outcomes as compared to a more restrictive strategy.We will enroll 3500 patients with acute MI (type 1, 2, 4b or 4c) as defined by the Third Universal Definition of MI and a hemoglobin10 g/dL at 144 centers in the United States, Canada, France, Brazil, New Zealand, and Australia. We randomly assign trial participants to a liberal or restrictive transfusion strategy. Participants assigned to the liberal strategy receive transfusion of RBCs sufficient to raise their hemoglobin to at least 10 g/dL. Participants assigned to the restrictive strategy are permitted to receive transfusion of RBCs if the hemoglobin falls below 8 g/dL or for persistent angina despite medical therapy. We will contact each participant at 30 days to assess clinical outcomes and at 180 days to ascertain vital status. The primary endpoint is a composite of all-cause death or recurrent MI through 30 days following randomization. Secondary endpoints include all-cause mortality at 30 days, recurrent adjudicated MI, and the composite outcome of all-cause mortality, nonfatal recurrent MI, ischemia driven unscheduled coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting), or readmission to the hospital for ischemic cardiac diagnosis within 30 days. The trial will assess multiple tertiary endpoints.The MINT trial will inform RBC transfusion practice in patients with acute MI.

Context.— ABO mistransfusions are rare and potentially fatal events. Protocols are required by regulatory agencies to minimize this risk to patients, but how these are applied in the context of massive transfusion protocols (MTPs) is not specifically defined. Objective.— To evaluate the approaches used by transfusion services for switching from universally compatible to patient ABO type-specific blood components during massive hemorrhage. Design.— We added 1 supplemental multiple-choice question to address the study objective to the 2019 College of American Pathologists proficiency test J-survey (J-A 2019). We also reviewed the available literature regarding this topic. Results.— A total of 881 laboratories responded to the supplemental question. Approximately 80% (704 of 881) reported a policy for ABO-type switching during an MTP. Policies varied considerably between responding laboratories, but most (384 of 704, 55%) required 2 ABO types to match before switching from universal to recipient-specific blood components. Additional safety measures used in a minority of these protocols included reaction strength criteria (103 of 704, 15%), on-call medical director approval (41 0f 704, 5.8%), universal red cell unit number limits (12 of 704, 1.7%), or the presence of a mixed field (3 of 704, 0.4%). Conclusions.— This survey reveals that significant heterogeneity exists regarding the available approaches for ABO-type switching during an MTP. Specific expert guidance regarding this issue is very limited, and best practices have not yet been established or rigorously investigated.

BACKGROUND The introduction of therapeutic plasma exchange (TPE) dramatically decreased mortality in patients with immune thrombotic thrombocytopenic purpura (iTTP). However, there are few modern descriptions of residual causes of death from iTTP and complications associated with TPE. STUDY DESIGN AND METHODS This was a retrospective study in a multi-institutional cohort of 109 patients with iTTP between 2004 and 2017. Complications of TPE were analyzed in a subset of this cohort (74 patients representing 101 treatment courses). RESULTS Death occurred in 8 of 109 patients (7.3%) and in 8 of 219 captured episodes of acute iTTP (mortality rate per episode: 3.7%). Neither the number of TPE treatments nor length of hospitalization predicted mortality. The majority of deaths (5/8) were associated with delay in the diagnosis of iTTP or initiation of TPE or presentation to the hospital in a moribund state. A subset of patients (N = 74) was analyzed for TPE-related complications. Most patients (56/74; 76%) had at least one minor or major complication of TPE. Seven of 101 (6.9%) discrete treatment courses were associated with one or more severe complications, including anaphylaxis and line-associated infections and thrombosis. Overall, the most frequent adverse events were mild allergic (urticarial) transfusion reactions, which affected 34 of 101 (34%) treatment courses. One patient died from a TPE-related complication, line-associated bacteremia. CONCLUSION Early identification of patients with iTTP and the rapid initiation of TPE are paramount in preventing mortality. While TPE was associated with a high rate of adverse events, the vast majority were treatable and TPE-related mortality is low.

Patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) often experience life-threatening relapses of the disease, and rituximab (RTX) can be used to mitigate relapse risk. However, the predictors of relapse in iTTP and the magnitude and duration of effect of RTX remain key unanswered questions. Using a multi-institutional cohort of consecutive adult patients with iTTP, we used survival analysis to compare relapse rates between patients who received RTX during the index presentation with acute iTTP and those who did not. Of 124 patients, 60 (48%) received RTX and 34 (27%) experienced relapse. Median time to relapse was 3.71 (interquartile range, 1.75-4.9) and 1.33 (interquartile range, 0.43-2.35) years for RTX-treated and untreated patients, respectively. RTX conferred protection from relapse at 1 year of follow-up (P = .01) but not at 5 years of follow-up. Extended Cox regression was then used to identify predictors of relapse and to estimate the protective effect of RTX. The following parameters were independently associated with increased risk for subsequent relapse: presenting in iTTP relapse (hazard ratio [HR], 2.97; 95% confidence interval [CI], 1.4-6.4), age younger than 25 years (HR, 2.94; 95% CI, 1.2-7.2), and non-O blood group (HR, 2.15; 95% CI, 1.06-4.39). RTX initially provided protection from relapse (HR, 0.16; 95% CI, 0.04-0.70), but this effect gradually diminished, returning to the baseline risk for untreated patients at approximately 2.6 years. Patients who are young, have non-O blood group, or present with relapsed iTTP are at increased risk for subsequent relapse. RTX appears to confer short-term protection from relapse.

Purpose of review This review is a critical appraisal of the current data comparing restrictive vs. liberal transfusion strategies for patients who are critically ill in ICUs. We focus on four subsets of critically ill patients: pediatric patients, patients with gastrointestinal bleeds, septic patients and patients undergoing cardiac surgery. Recent findings Almost a decade after the TRICC trial, a randomized trial showing the safety of a restrictive transfusion threshold in critically ill patients, four large randomized controlled trials have shown that a restrictive transfusion strategy is safe in pediatric critically ill patients, patients with acute upper gastrointestinal bleeds, patients with septic shock and patients undergoing cardiac surgery. A large multicenter randomized trial is underway to determine the safety of a restrictive strategy in myocardial infarction. Summary A restrictive transfusion threshold is recommended in nearly all critically ill patients. This is at least noninferior to more liberal transfusion practice; in addition, a restrictive threshold has shown improved outcomes in some patients and decreased chances of adverse events in patients. Judicious use of red cells improves patient outcome and protects the blood supply, a limited resource. More data are needed to determine appropriate transfusion threshold recommendations for patients with traumatic brain injury and acute coronary syndrome.

Immunoassays are commonly used by the clinical laboratory, but paraproteins can occasionally produce erroneous results. In this study, we investigated the cause of apparent false positive results for multiple Kinetic Interaction of Microparticles in Solution (KIMS) immunoassays. Patient controls and samples containing the interference were analyzed using automated chemistry platforms, gel electrophoresis, immunofixation, affinity chromatography, and size exclusion chromatography. Our results show that IgA paraprotein caused false positive results for the KIMS measurement of three therapeutic drugs. To our knowledge, this is the first report of IgA paraprotein-causing immunoassay interference. The clinical implications of this interference are discussed.

Background and objectives Judicious utilization of platelet products protects a limited resource and mitigates risks of transfusion. At many institutions, computer physician order entry systems provide prompts to guide transfusion decisions; many capture the indication for transfusion, and generate metadata when orders are dissonant with guidelines. We conducted a retrospective review to examine adherence to and overrides of hospital guidelines for platelet transfusion to identify opportunities for improved transfusion practice. Materials and methods Physician override reports (1/1/2018-3/31/2019) were examined and physician-entered justification comments accompanying override orders were extracted, in addition to patient-specific data (clinical service, age, sex, and pretransfusion platelet count). Two transfusion medicine physicians independently assessed comments in context of patient data and institutional guidelines and categorized as: indicated, protocol driven, or not indicated. Following adjudication, consensus was reached between the two reviewers. Override keyword frequencies were also determined. Results Over 15-months, 1373 override orders were placed for 558 unique patients (25% of all adult inpatient platelet transfusions). haematology/oncology providers placed 573 (42%) override orders (261 unique patients), 46% of which were categorized as "not indicated", based on consensus review. Overall, 470 (34%) override orders were categorized as "not indicated". Examples of recurring key words included "bleeding/risk of bleeding", "falling platelet count", "platelet goal of XX". Conclusions A large percentage of override orders for platelet transfusions were determined to be "not indicated" and out of compliance with institutional guidelines. The metadata captured identified concerns regarding clinical transfusion practice and opportunities for revised indications (e.g. threshold for retinal haemorrhage).

The objective of this study was to examine the predictive value of fibrinogen concentration for bleeding complications among women presenting for delivery and for whom a fibrinogen level was measured before delivery.This was a nested case-control study using a cohort of all women who delivered at our institution from October 2001 to July 2016 and in whom a fibrinogen concentration was obtained within 48 hours before delivery. We identified all cases that had one or more of the following events: (1) postpartum hemorrhage; (2) postpartum hysterectomy; (3) transfusion of select blood products; or (4) a ≥ 33% decrease in hematocrit from the first hematocrit measured during the hospital stay to any subsequent hematocrit value drawn either simultaneously with or following the fibrinogen concentration measurement. We included the first case or control delivery for a given woman. Controls were the next one or two consecutive deliveries without a bleeding complication and matched for number of fetuses. We used logistic regression to calculate the odds ratio and 95% confidence intervals and calculated the area under the receiver operating characteristic curve.We identified 424 cases and 801 controls. The mean predelivery fibrinogen concentration was significantly lower in cases (425 ± 170 mg/dL) than controls (523 ± 122 ng/mL) for all case types combined (Antepartum fibrinogen concentration was significantly lower among women who developed bleeding complications, though these differences may not be large enough to provide clinically meaningful critical values. Nevertheless, a higher threshold for the critical value during pregnancy should be considered.

In a prior phase 2 study, personalized cancer vaccination with autologous dendritic cells (DCs) fused with primary MM tumor cells (DC/MM fusions) induced the expansion of circulating MM-reactive lymphocytes and was associated with conversion to complete response (CR) post-autoHCT in the absence of maintenance therapy. 1 We now present a multicenter randomized phase II study that examined the efficacy of DC/MM fusion vaccination with lenalidomide maintenance therapy after autoHCT, compared with lenalidomide maintenance alone. The study offered a first-of-its-kind academic collaborative effort of personalized cell therapy using an open-source format, site-specific production, and centralized product characterization/release criteria verification. Under the aegis of the BMT CTN (CTN 1401), 203 patients enrolled from 18 participating centers. Sixty-three patients dropped out of the study from enrollment to randomization for an overall dropout rate of 31%, concordant with the expected rate of 30% pre-specified in the protocol. Among the 140 patients, 68 were randomized to the vaccine arm, 37 to the lenalidomide/GM-CSF arm, and 35 to the lenalidomide alone arm. Ninety-one (65.0%) patients had high-risk MM. A collaborative process was established for the standardization of vaccine manufacturing including tumor cell harvest and cryopreservation, DC generation from leukapheresis collection, creation and quantification of the DC/tumor fusion vaccine, and the process of characterizing each cellular product. Of the 140 patients who underwent tumor collection, the median percentage of plasma cells in bone marrow aspirate differential was 45%. Mean CD86 expression and viability of the DC preparations were 80.6% and 79.3%, respectively. The mean fusion efficiency of the DC/MM product, as determined by co-expression of standard DC (CD86) and MM (CD38) markers, was 47.9%. Mean fusion cell viability was 78.6%. Vaccine was successfully generated for 63/68 patients (93%) assigned to the vaccine arm of the study. Thirty-six of the 68 (52.9%) evaluable patients on the vaccine arm (80% confidence interval 44.5%, 61.3%) and 34 of the 68 (50.0%) of the non-vaccine arms (80% confidence interval 41.6%, 58.4%) achieved CR/sCR at 1-year post-transplant (p=0.3). Of the patients not achieving CR at time of randomization post-transplant, conversion to CR at 1-year was 34.8% for the vaccine arm and 27.3% for the non-vaccine arm (p=0.4). sCR/CR/VGPR at 1-year was achieved by 85.3% and 77.8% of patients on the vaccine and non-vaccine arms, respectively (p=0.2). The rates of post-transplant grade 3-4 toxicities were 76.5%, 62.5% for the vaccine, and non-vaccine arms, respectively (p=0.07). There were no grade 5 toxicities in any of the cohorts. The overall grade 2-3 infection rate was 22.9% (23.5% on the vaccine arm, 13.5% on the lenalidomide/GM-CSF arm, and 31.4% on the lenalidomide alone arm). Quantification of circulating MM-reactive T cells was performed for an initial cohort of 20 patients who completed 1-year post-transplant assessments. Patients in the vaccine arm demonstrated a significant expansion of MM-reactive CD8 cells, representing 2.9%, 3.5%, and 15.9% of the lymphocyte population prior to post-transplant maintenance, following 1 cycle of lenalidomide and following 3 vaccinations at 1-year post-transplant, respectively (Figure). In contrast, there was no increase in MM-specific CD8 T cells in the control arm with levels of 1.1, 2.0. and 0.6, respectively. Single-cell transcriptomic analysis performed on the peripheral T-cell repertoire of 14 patients from the vaccine arm at serial time points demonstrated progressive expansion of dominant CD8, CD4, and NKT cell clones with an activated phenotype. Vaccination was associated with the recovery of T-cell clonal diversity. This multicenter trial demonstrated successful site-specific production. DC/MM fusion vaccination with lenalidomide maintenance after autoHCT did not result in a significant increase in CR rates at 1-year but was associated with measurable anti-MM immune reactivity for which the impact on response duration will require longer term follow-up. 1. Rosenblatt, J. et al. Vaccination with dendritic cell/tumor fusions following autologous stem cell transplant induces immunologic and clinical responses in multiple myeloma patients. Clin. Cancer Res. 19, 3640-3648 (2013) Figure 1 Figure 1. Disclosures Shah: CareDx: Consultancy; GSK: Consultancy; Teneobio: Research Funding; Kite: Consultancy; Nektar: Research Funding; Poseida: Research Funding; Oncopeptides: Consultancy; Bluebird Bio: Research Funding; CSL Behring: Consultancy; Indapta Therapeutics: Consultancy; Janssen: Research Funding; Sanofi: Consultancy; Sutro Biopharma: Research Funding; Precision Biosciences: Research Funding; BMS/Celgene: Research Funding; Karyopharm: Consultancy; Amgen: Consultancy. Stroopinsky: The Blackstone Group: Consultancy. Anderson: Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees. Devine: Magenta Therapeutics: Current Employment, Research Funding; Tmunity: Current Employment, Research Funding; Johnsonand Johnson: Consultancy, Research Funding; Orca Bio: Consultancy, Research Funding; Be the Match: Current Employment; Sanofi: Consultancy, Research Funding; Vor Bio: Research Funding; Kiadis: Consultancy, Research Funding. Holmberg: Sanofi: Research Funding; Millennium-Takeda: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Merck: Research Funding; Janssen: Research Funding; Up-To-Date: Patents & Royalties. Johnson: Miltenyi Biotec: Research Funding. Lazarus: Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees. Malek: Janssen: Other: Advisory board ; Medpacto Inc.: Research Funding; Takeda: Honoraria; BMS: Honoraria, Research Funding; Amgen: Honoraria; Cumberland Inc.: Research Funding; Bluespark Inc.: Research Funding; Sanofi: Other: Advisory Board. McCarthy: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, 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; Juno: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: 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. McKenna: Qihan Bio: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Other: all manufacturing of cell therapy products for clinical trials; Intima: Other: all manufacturing of cell therapy products for clinical trials; Gamida: Other: all manufacturing of cell therapy products for clinical trials; Magenta: Other: all manufacturing of cell therapy products for clinical trials. Munshi: Takeda: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Amgen: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Abbvie: Consultancy; Adaptive Biotechnology: Consultancy; Legend: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy. Nooka: Janssen Oncology: Consultancy, Research Funding; Adaptive technologies: Consultancy; Sanofi: Consultancy; GlaxoSmithKline: Consultancy, Other: Travel expenses; Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding; Oncopeptides: Consultancy; Karyopharm Therapeutics: Consultancy. Soiffer: Jazz Pharmaceuticals, USA: Consultancy; Precision Biosciences, USA: Consultancy; Juno Therapeutics, USA: Other: Data Safety Monitoring Board; Kiadis, Netherlands: Membership on an entity's Board of Directors or advisory committees; Rheos Therapeutics, USA: Consultancy; Gilead, USA: Other: Career Development Award Committee; NMPD - Be the Match, USA: Membership on an entity's Board of Directors or advisory committees; Jasper: Consultancy; Takeda: Consultancy. Uhl: Grifols: Consultancy, Speakers Bureau; Abbott: Consultancy, Speakers Bureau; UpToDate: Patents & Royalties. Young: Amgen: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company. Rosenblatt: Attivare Therapeutics: Consultancy; Bristol-Myers Squibb: Research Funding; Parexel: Consultancy; Wolters Kluwer Health: Consultancy, Patents & Royalties; Imaging Endpoints: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Waller: Verastem Oncology: Consultancy, Research Funding; Cambium Oncology: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Pasquini: GlaxoSmithKline: Research Funding; Kite Pharma: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Avigan: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Consultancy, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Partner Tx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Aviv MedTech Ltd: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Parexcel: Consultancy; Takeda: Consultancy; Sanofi: Consultancy. OffLabel Disclosure: Dendritic Cell/Tumor Fusion Vaccine and GM-CSF

Background. Platelet transfusion is a critical therapy for hematology-oncology patients at risk of transfusion-transmitted infection (TTI) and pulmonary injury. Amotosalen-UVA pathogen reduction (PR) treatment of apheresis platelet components (PC) in plasma or additive solution (INTERCEPT Blood System for Platelets, Cerus, Concord, CA) is FDA approved to reduce risk of TTI and transfusion associated graft vs. host disease (TA-GVHD). PRPC meet the FDA bacteria risk reduction guidance, and approximately 50% of U.S. PC are PRPC. Amotosalen-UVA PR replaces bacteria screening, gamma irradiation, and CMV serology. PR is performed within 24 hours of collection enabling early release of PRPC with 5-day storage. We tested the hypothesis that PRPC were not inferior to conventional PC(CPC) for the incidence of pulmonary injury. Methods. An open-label sequential cohort study in platelet transfusion dependent hematology-oncology patients was conducted under routine practice conditions in 15 clinical centers. Each site enrolled a CPC cohort followed by a PRPC cohort using 4 primary therapy strata matched ± 10%: chemotherapy without hematopoietic cell transplant (HCT), HCT with myeloablation, HCT with non-myeloablative conditioning, and HCT with reduced intensity conditioning (RIC). Patients were supported with the assigned PC type for up to 21 days with 7 days of surveillance after the last PC exposure. Patients participated in only one cohort. The primary endpoint was treatment emergent assisted mechanical ventilation (TEAMV) by intubation or tight mask with positive end expiration pressure (5cm H 2O) after initiation of study PC. All endpoint patients were adjudicated by a blinded pulmonary expert panel (PEP) for diagnosis of acute respiratory distress syndrome (ARDS) by the Berlin Criteria. Secondary endpoints included: time to initiation of TEAMV, clinically significant pulmonary adverse events (CSPAE, CTCAE ≥ Grade 2), transfusion reactions, and mortality. The incidence of TEAMV by non-inferiority (margin = 2.3%), and secondary endpoints were analyzed by modified intention to treat (mITT) and per protocol (PP). Sensitivity analyses with propensity score matching for key variables were conducted for the primary endpoint. The associations between PC and categorical variables were tested by stratified Cochran-Mantel-Haenszel and continuous variables by ANOVA for two-sided significance p = 0.05. results. A total of 2291 pediatric and adult patients (1068 PRPC and 1223 CPC) were enrolled in the respective cohorts with transfusion of 5,277 PRPC and 5,491 CPC. PC assignment compliance and study completion were > 94%. For the mITT data set, the cumulative incidence of TEAMV was lower for the PRPC cohort (log rank p = 0.039) than the CPC cohort (2.9% versus 4.6%, HR = 0.633: 95% CI 0.408-0.982). PRPC by mITT were non-inferior to CPC for the incidence of TEAMV due to all indications, and for TEAMV with pulmonary dysfunction (PD) by PEP (Table). PP analyses were consistent with mITT. Relative risk (RR) of TEAMV showed significantly (p Figure 1 Figure 1. Disclosures Wheeler: Novo Nordisk A/S: Consultancy; Bayer: Consultancy; BioMarin: Consultancy; HEMA Biologics: Consultancy; Spark: Consultancy; Takeda: Consultancy; UniQure: Consultancy. Nooka: Janssen Oncology: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Oncopeptides: Consultancy; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Adaptive technologies: Consultancy; GlaxoSmithKline: Consultancy, Other: Travel expenses; Karyopharm Therapeutics: Consultancy. Uhl: UpToDate: Patents & Royalties; Abbott: Consultancy, Speakers Bureau; Grifols: Consultancy, Speakers Bureau. Spinella: Secure Transfusion Services: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Cerus Corporation: Consultancy, Research Funding. Liu: Cerus Corporation: Current Employment, Current equity holder in publicly-traded company. Benjamin: Cerus Corporation: Current Employment, Current equity holder in publicly-traded company. Corash: Cerus Corporation: Current Employment, Current equity holder in publicly-traded company.

BACKGROUND The a disintegrin and metalloprotease with thrombospondin type 1 motifs, member 13 (ADAMTS13) activity assay has become important in distinguishing autoimmune thrombotic thrombocytopenic purpura from other forms of thrombotic microangiopathy (TMA). Although the significance of severe deficiency in ADAMTS13 (activity levels 10% or less) has been well defined, little data are available on the clinical importance of mild to moderate deficiency (activity levels 11%-70%) among patients with TMA. STUDY DESIGN AND METHODS We conducted a retrospective study using the Harvard TMA Research Collaborative Registry. Among 254 patients who met the inclusion criteria for TMA, 186 patients with ADAMTS13 activity levels greater than 10% were divided into moderate-deficiency (11%-40%), mild-deficiency (41%-70%), and no-deficiency (greater than 70%). RESULTS Compared with mild or no deficiency, moderate ADAMTS13 deficiency correlated with older age; higher bilirubin and international normalized ratio; and increased frequency of sepsis, shock, or multiorgan failure. Platelet counts, lactate dehydrogenase levels, and the presence of renal or neurologic dysfunction did not vary across the three patient cohorts. While moderate ADAMTS13 deficiency was associated with increased 90-day mortality in univariate analysis, this association was no longer significant in multivariate analysis. Variables that independetly predicted 90-day mortality in this cohort of patients included Charlson comorbidity index, alanine aminotransferase level, platelet count, creatinine, and the presence of sepsis, shock, or multiorgan failure. CONCLUSION Moderately deficient ADAMTS13 activity identifies a cohort of patients with TMA who are at increased risk for 90-day mortality. The ADAMTS13 activity level in this group is not an independent predictor of poor outcomes but instead appears to be a marker of disease acuity.

BMT CTN 1401 is an academically led randomized study of a personalized cancer vaccine in which the combination of DC/MM fusion vaccine and lenalidomide maintenance after autoHCT is compared with maintenance alone as upfront treatment of MM (NCT#02728102). Assessment of the percentage of patients achieving CR and therapy-induced changes in MM-specific immunity are the primary clinical and immunologic endpoints, respectively. The protocol represents a transformative open source approach to cell therapy in MM and required collection of tumor cells prior to treatment initiation and vaccine production at day 60 after autoHCT. The process featured a multi-step approach of procedural standardization, training, and centralized verification of manufactured product/release criteria. Here we present initial analysis of accrual and vaccine manufacturing. Enrollment of 203 patients completed within 26 months with 140 patients randomized. Drop-out rate from enrollment to randomization was 31% (expected 30%). Sixty-eight patients were randomized to the DC/MM fusion vaccine arm, with 63 having products successfully manufactured and approved for release at 14 manufacturing sites. Vaccine products for 5 patients were not approved for release for the following reasons: final TC/DC viability did not meet release criteria (n = 3), product failed to meet sterility release criteria (n = 1), and disease progression prior to manufacture (n = 1). Among 63 participants who received vaccine, mean DC viability and CD86 expression was 79.3% (Standard Deviation = 11.3) and 80.6% (SD = 12.9), respectively. Mean viability and percent cells co-expressing DC and tumor antigens was 78.6% (SD = 13.0) and 47.9% (SD = 11.4), respectively. The process devised for BMT CTN 1401 led to rapid patient accrual and successful point-of-care DC/MM fusion vaccine generation. Feasibility of serial sample collection and performance of immunologic correlates were demonstrated. This multi-center collaboration highlights the development of a personalized tumor vaccine platform that serves as a model for future immunotherapy trials in MM.

The PLASMIC score is a recently described clinical scoring algorithm that rapidly assesses the probability of severe ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency among patients presenting with microangiopathic haemolytic anaemia. Using a large multi-institutional cohort, we explored whether an approach utilizing the PLASMIC score to risk-stratify patients with suspected immune thrombotic thrombocytopenic purpura (iTTP) could lead to significant cost savings. Our consortium consists of institutions with an unrestricted approach to ADAMTS13 testing (Group A) and those that require pre-approval by the transfusion medicine service (Group B). Institutions in Group A tested more patients than those in Group B (P < 0·001) but did not identify more cases of iTTP (P = 0·29) or have lower iTTP-related mortality (P = 0·84). Decision tree cost analysis showed that applying a PLASMIC score-based strategy to screen patients for ADAMTS13 testing in Group A would have reduced costs by approximately 27% over the 12-year period of our study compared to the current approach. Savings were primarily driven by a reduction in unnecessary therapeutic plasma exchanges, but lower utilization of ADAMTS13 testing and subspecialty consultations also contributed. Our data indicate that using the PLASMIC score to guide ADAMTS13 testing and the management of patients with suspected iTTP could be associated with significant cost savings.

A collaboration that grew over time between local hemovigilance stakeholders and the Massachusetts Department of Public Health (MDPH) resulted in the change from a paper-based method of reporting adverse reactions and monthly transfusion activity for regulatory compliance purposes to statewide adoption of electronic reporting via the National Healthcare Safety Network (NHSN). The NHSN is a web-based surveillance system that offers the capacity to capture transfusion-related adverse events, incidents, and monthly transfusion statistics from participating facilities. Massachusetts' hospital blood banks share the data they enter into NHSN with the MDPH to satisfy reporting requirements. Users of the NHSN Hemovigilance Module adhere to specified data entry guidelines, resulting in data that are comparable and standardized. Keys to successful statewide adoption of this reporting method include the fostering of strong partnerships with local hemovigilance champions and experts, engagement of regulatory and epidemiology divisions at the state health department, the leveraging of existing relationships with hospital NHSN administrators, and the existence of a regulatory deadline for implementation. Although limitations exist, successful implementation of statewide use of the NHSN Hemovigilance Module for hospital blood bank reporting is possible. The result is standardized, actionable data at both the hospital and state level that can facilitate interfacility comparisons, benchmarking, and opportunities for practice improvement.

Obstetric hemorrhage remains a leading cause of maternal mortality with more than 140,000 deaths annually worldwide. Abnormal placentation has increased to become the most common diagnosis requiring massive blood transfusion in obstetrics, with uterine atony a close second. At our institution, as well as nationwide, there has been a steady increase in pregnancies complicated by abnormal placentation, including accreta, increta, and percreta. Providers at our facility created the New England Center for Placental Disorders in May 2015 to address these complex patients. The incidence of accreta has actually increased 10-fold over the past 50 years, becoming the most common reason for cesarean hysterectomy in highly industrialized countries. The most common risk factor for accreta is repeat cesarean sections, particularly those with associated placenta previa. Contemporary cesarean section rates have risen, with more than 1.2 million women having had a cesarean section in the United States in 2014. We present a case vignette of a multiparous woman presenting with heavy vaginal bleeding at 30 weeks' gestation with imaging concerning for placenta accreta and possible percreta. We describe our approach to the management of these complicated patients.

BACKGROUND Therapeutic plasma exchange (TPE) is a proven treatment for thrombotic thrombocytopenic purpura (TTP) characterized by severe ADAMTS13 deficiency, but the efficacy of TPE in suspected TTP with an ADAMTS13 activity level of more than 10% remains controversial. STUDY DESIGN AND METHODS We conducted a propensity score (PS)-matched study of 186 adult patients included in the Harvard Thrombotic Microangiopathy (TMA) Research Collaborative registry who presented with TMA suggestive of TTP but an ADAMTS13 activity level of more than 10%. RESULTS Before matching, patients treated with TPE (n = 71) differed from untreated patients (n = 115) by several clinical measures. PS matching was performed to address clinical disparities between the two groups and resulted in a well-balanced cohort of 59 TPE-treated patients paired with 59 untreated controls, all of whom had TMA. After matching, we observed no significant difference in the primary outcome of 90-day survival between the treated and untreated groups (hazard ratio, 0.88; 95% confidence interval [CI], 0.44-1.77; p = 0.72). In-hospital mortality (odds ratio [OR], 0.77; 95% CI, 0.34-1.75; p = 0.53) and the percentage of patients with platelet count recovery (OR, 1.58; 95% CI, 0.77-3.26; p = 0.21) also did not differ significantly between the two matched groups. CONCLUSION Our data suggest that routine use of TPE in the diverse group of TMA patients without severe ADAMTS13 deficiency may not significantly improve outcomes.

Background The pneumatic tube delivery system (PTDS) has been an integral part of blood bank (BB) operations at our institution ever since its implementation in the early 2000s. Its reliable performance is essential for rapid and accurate delivery of blood products, impacting patient safety and product integrity. However, malfunctioning operational events are not uncommon given PTDS complexity and hospital-wide utilization. In 2018, 33 of 285 (12%) blood products were wasted due to PTDS events at our institution. Here we review the root cause analysis (RCA) of a patient safety event involving delayed transfusions and a wasted blood product causing temporary harm to two patients. Methods Two patients, both hospitalized on the same floor, simultaneously experienced significant delays in red blood cell (RBC) transfusions. One patient with active bleeding experienced a 2-hour delay and another patient with anemia experienced a 50-minute delay before appropriate transfusion occurred. The two patients did not receive their transfusions until their nurses physically retrieved RBC units from the BB. An incident report was filed by a floor nurse, which prompted a RCA involving the laboratory quality and patient safety team, the BB, the hospital maintenance department overseeing the PTDS, and the information systems service controlling programming of the PTDS. Results Operational challenges surrounding the PTDS were central to the multiple root causes identified (see Table). RBC units sent to the floor from the BB were electronically directed to another floor or returned to the BB, which resulted in a waste of one RBC unit. Despite multiple potential contributing factors identified, deeper investigation did not uncover evidence for any specific root cause and the electronic tube transaction history showed normal PTDS operations during the time of the incident, with all transactions appearing as successfully completed within expected timeframes. Neither of the patients involved in this safety event experienced permanent harm. The findings of this investigation were reviewed at our departmental Pathology Morbidity and Mortality conference together with stakeholders from hospital maintenance. Conclusion The root causes for PTDS technical malfunctioning leading to this safety event remain uncertain despite a collaborative RCA. This multidisciplinary retrospective RCA process, however, provided an opportunity for greater awareness of the complex mechanism of the PTDS, promoted awareness of the roles of the various stakeholders involved, and fostered interdepartmental collaboration to prevent future patient safety incidents using quality improvement principles. Table Disclosures No relevant conflicts of interest to declare.

The Harvard TMA Research Collaborative is a multi-institutional registry-based effort to study thrombotic microangiopathies (TMA). Laboratory and clinical parameters were recorded for 254 cases of suspected autoimmune thrombotic thrombocytopenic purpura (TTP). Patients with severe ADAMTS13 deficiency (activity ≤10%, N = 68) were more likely to be young, female and without a history of cancer treatment or transplantation. While all patients with severe deficiency were diagnosed with autoimmune TTP, those without severe deficiency frequently had disseminated intravascular coagulation, drug-associated TMA and transplant-related TMA. Patients with severe ADAMTS13 deficiency had superior overall survival at 360 d compared to those without severe deficiency (93·0% vs. 47·5%, P 0·0001). Almost all patients with severe deficiency received therapeutic plasma exchange (TPE), but the use of TPE in patients with ADAMTS13 activity10% varied significantly across the institutions in our consortium (13·2-63·8%, P 0·0001). Nevertheless, 90-d mortality was not different in patients with ADAMTS13 activity10% between the three hospitals (P = 0·98). Our data show that patients with severe ADAMTS13 deficiency represent a clinically distinct cohort that responds well to TPE. In contrast, TMA without severe ADAMTS13 deficiency is associated with increased mortality that may not be influenced by TPE.

Some observational studies have reported that transfusion of red-cell units that have been stored for more than 2 to 3 weeks is associated with serious, even fatal, adverse events. Patients undergoing cardiac surgery may be especially vulnerable to the adverse effects of transfusion.We conducted a randomized trial at multiple sites from 2010 to 2014. Participants 12 years of age or older who were undergoing complex cardiac surgery and were likely to undergo transfusion of red cells were randomly assigned to receive leukocyte-reduced red cells stored for 10 days or less (shorter-term storage group) or for 21 days or more (longer-term storage group) for all intraoperative and postoperative transfusions. The primary outcome was the change in Multiple Organ Dysfunction Score (MODS; range, 0 to 24, with higher scores indicating more severe organ dysfunction) from the preoperative score to the highest composite score through day 7 or the time of death or discharge.The median storage time of red-cell units provided to the 1098 participants who received red-cell transfusion was 7 days in the shorter-term storage group and 28 days in the longer-term storage group. The mean change in MODS was an increase of 8.5 and 8.7 points, respectively (95% confidence interval for the difference, -0.6 to 0.3; P=0.44). The 7-day mortality was 2.8% in the shorter-term storage group and 2.0% in the longer-term storage group (P=0.43); 28-day mortality was 4.4% and 5.3%, respectively (P=0.57). Adverse events did not differ significantly between groups except that hyperbilirubinemia was more common in the longer-term storage group.The duration of red-cell storage was not associated with significant differences in the change in MODS. We did not find that the transfusion of red cells stored for 10 days or less was superior to the transfusion of red cells stored for 21 days or more among patients 12 years of age or older who were undergoing complex cardiac surgery. (Funded by the National Heart, Lung, and Blood Institute; RECESS ClinicalTrials.gov number, NCT00991341.).

Background AABB Standard 5.27 requires transfusion services to have a process for urgent release of blood before completion of compatibility testing. Our institution endorses a policy for the emergency release of group O, D+ red blood cells (RBC; O+ RBC) to males and females at least 50 years of age. Our emergency department (ED) stocks 4 O− RBC units. To determine if O+ RBCs can replace ED O− RBCs, we performed a retrospective review. Study Design and Methods Patients admitted to the ED between January 2001 and August 2011 and transfused emergency-release O− RBCs were identified. Data were collected on sex, age, length of stay, clinical status, ABO/Rh, RBC transfusions, and RBC antibody screen results. Results A total of 498 ED O− RBC units were transfused to 268 patients (168 male, 100 female). A total of 322 units were transfused to males and 114 to females at least 50 years of age. Thirty-nine (14%) were D− with 18 receiving O+ RBCs. A total of 109 had follow-up antibody screens; one D− patient developed alloanti-D. Conclusions The findings support the placement of O+ RBCs in the ED. The majority of ED O− RBCs (88%) went to patients who qualified for O+ RBCs; a minority (1.5%) of patients were D− females less than 50 years of age. The rate of alloimmunization was low.

This review summarizes the salient points of the symposium ‘Red Cell Genotyping 2015: Precision Medicine’ held on 10 September 2015 in the Masur Auditorium of the National Institutes of Health. The specific aims of this 6th annual symposium were to: (1) discuss how advances in molecular immunohematology are changing patient care; (2) exemplify patient care strategies by case reports (clinical vignettes); (3) review the basic molecular studies and their current implications in clinical practice; (4) identify red cell genotyping strategies to prevent alloimmunization; and (5) compare and contrast future options of red cell genotyping in precision transfusion medicine. This symposium summary captured the state of the art of red cell genotyping and its contribution to the practice of precision medicine.

Bleeding remains a significant problem for many thrombocytopenic hematology/oncology patients in spite of platelet transfusions. Factors that might contribute to bleeding were analyzed for 16 320 patient-days on or after their first platelet transfusion in 1077 adult patients enrolled in the Platelet Dose (PLADO) trial. All patients had a greatly increased risk of bleeding at platelet counts of ≤5 × 109/L (odds ratio [OR], 3.1; 95% confidence interval [CI], 2.0-4.8) compared with platelet counts ≥81 × 109/L. Platelet counts between 6 × 109/L and 80 × 109/L were also associated with a somewhat elevated bleeding risk in patients receiving allogeneic stem cell transplants (SCTs) or chemotherapy but not in those undergoing autologous SCTs. Other significant laboratory predictors of bleeding were hematocrit ≤25% (OR, 1.29; 95% CI, 1.11-1.49), activated partial thromboplastin time (aPTT) 30 to ≤50 seconds (OR, 1.40; 95% CI, 1.08-1.81; P = .01), aPTT >50 seconds (OR, 2.34; 95% CI, 1.54-3.56), international normalized ratio (INR) 1.2 to 1.5 (OR, 1.46; 95% CI, 1.17-1.83), and INR >1.5 (OR, 2.05; 95% CI, 1.43-2.95). Transfusion of either platelets or red blood cells (RBCs) on days with bleeding was often not sufficient to change bleeding outcomes on the following day. Because bleeding occurred over a wide range of platelet counts among patients undergoing allogeneic SCT or chemotherapy and because platelet transfusions may not prevent bleeding, other risk factors may be involved. These may include low hematocrit and coagulation abnormalities. This trial was registered at www.clinicaltrials.gov as #NCT00128713.

The a disintegrin and metalloprotease with thrombospondin type 1 motifs, member 13 (ADAMTS13) activity assay has become important in distinguishing autoimmune thrombotic thrombocytopenic purpura from other forms of thrombotic microangiopathy (TMA). Although the significance of severe deficiency in ADAMTS13 (activity levels 10% or less) has been well defined, little data are available on the clinical importance of mild to moderate deficiency (activity levels 11%-70%) among patients with TMA.We conducted a retrospective study using the Harvard TMA Research Collaborative Registry. Among 254 patients who met the inclusion criteria for TMA, 186 patients with ADAMTS13 activity levels greater than 10% were divided into moderate-deficiency (11%-40%), mild-deficiency (41%-70%), and no-deficiency (greater than 70%).Compared with mild or no deficiency, moderate ADAMTS13 deficiency correlated with older age; higher bilirubin and international normalized ratio; and increased frequency of sepsis, shock, or multiorgan failure. Platelet counts, lactate dehydrogenase levels, and the presence of renal or neurologic dysfunction did not vary across the three patient cohorts. While moderate ADAMTS13 deficiency was associated with increased 90-day mortality in univariate analysis, this association was no longer significant in multivariate analysis. Variables that independetly predicted 90-day mortality in this cohort of patients included Charlson comorbidity index, alanine aminotransferase level, platelet count, creatinine, and the presence of sepsis, shock, or multiorgan failure.Moderately deficient ADAMTS13 activity identifies a cohort of patients with TMA who are at increased risk for 90-day mortality. The ADAMTS13 activity level in this group is not an independent predictor of poor outcomes but instead appears to be a marker of disease acuity.

Background KEL1 alloimmunization is a major cause of hemolytic disease of the fetus and newborn (HDFN). While select countries have guidelines for preventing transfusion-associated KEL1 alloimmunization, the United States does not. Beth Israel Deaconess Medical Center instituted a policy in April 2009 whereby women not more than 50 years of age on the obstetric service were transfused KEL1-negative red blood cells (RBCs). We sought to determine compliance and impact for prevention of KEL1 alloimmunization and HDFN. Study Design and Methods All women not more than 50 years of age without anti-K transfused RBCs during an obstetric admission from April 9, 2009, to April 9, 2012, were identified (227). Adherence to policy, factors contributing to nonadherence, and subsequent impact were evaluated. For comparison, all cases of anti-K detection in women not more than 50 years of age admitted to nonobstetric services and all cases of transfusion-associated KEL1 alloimmunization in women not more than 50 years of age during the 10 years prior were identified. Results Eighty-four percent received only KEL1-negative units. Three (1.3%) women not more than 50 years of age on the obstetric service were identified with anti-K, while 17 (1.5%) women not more than 50 years of age on nonobstetric services had anti-K detected; only five of 20 had a prior RBC transfusion. In the 10 years prior, there were 27 cases of transfusion-associated KEL1 alloimmunization in women not more than 50 years of age. There were no cases of KEL1 HDFN in either period. Conclusion Although the findings demonstrate feasibility of providing KEL1-negative RBCs to women of childbearing potential, evidence for clinical benefit is lacking. The low prevalence of KEL1 in blood donors, the lack of significant differences in alloimmunization rates, and no cases of HDFN during the study period questions the clinical benefit of such a policy.

Among the syndromes characterised by thrombotic microangiopathy, thrombotic thrombocytopenic purpura is distinguished by a severe deficiency in the ADAMTS13 enzyme. Patients with this disorder need urgent treatment with plasma exchange. Because ADAMTS13 activity testing typically requires prolonged turnaround times and might be unavailable in resource-poor settings, a method to rapidly assess the likelihood of severe ADAMTS13 deficiency is needed.All consecutive adult patients presenting to three large academic medical centres in Boston, MA, USA, with thrombotic microangiopathy and a possible diagnosis of thrombotic thrombocytopenic purpura between Jan 8, 2004, and Dec 6, 2015, were included in an ongoing multi-institutional registry (the Harvard TMA Research Collaborative). Univariate analysis was used to identify covariates for a logistic regression model predictive of severe ADAMTS13 deficiency (≤10% activity). A clinical point score was generated, and its diagnostic performance was assessed using internal and external validation cohorts and compared to clinical assessment alone.214 patients with thrombotic microangiopathy were included in the derivation cohort. A seven-component clinical prediction tool, termed the PLASMIC score, was developed and found to reliably assess the pretest probability of severe ADAMTS13 deficiency (C statistic 0·96, 95% CI 0·92-0·98). Our diagnostic model was reproducibly accurate in both the internal (0·95, 0·91-0·98) and external (0·91, 0·85-0·95) validation cohorts. The scoring system also more consistently diagnosed thrombotic microangiopathy due to severe ADAMTS13 deficiency than did standard clinical assessment, as measured by C statistic (0·96, 95% CI 0·92-0·98 for PLASMIC vs 0·83, 0·77-0·88 for clinical assessment; p0·0001) and mean Brier score (0·065 for PLASMIC vs 0·111 for clinical assessment; mean paired difference 0·05, 95% CI 0·01-0·08; p0·0001). When utilised in addition to clinical assessment, the PLASMIC score contributed significant discriminatory power (integrated discrimination improvement 0·24, 95% CI 0·11-0·37).We have developed and validated a clinical prediction tool-the PLASMIC score-to stratify patients with thrombotic microangiopathy according to their risk of having severe ADAMTS13 deficiency. We have shown that this scoring system is superior to standard clinical assessment in addressing the diagnostic challenge presented by thrombotic microangiopathy. Its use, together with clinical judgment, may facilitate treatment decisions in patients for whom timely results of ADAMTS13 activity testing are unavailable.The Luick Family Fund of Massachusetts General Hospital.

We developed a personalized cancer vaccine in which patient-derived acute myeloid leukemia (AML) cells are fused with autologous dendritic cells, generating a hybridoma that potently stimulates broad antitumor responses. We report results obtained from the first 17 AML patients, who achieved remission after chemotherapy and were then serially vaccinated to target minimal residual disease and prevent relapse. Vaccination was well tolerated and induced inflammatory responses at the site of administration, characterized by the dense infiltration of T cells. Vaccination was also associated with a marked rise in circulating T cells recognizing whole AML cells and leukemia-specific antigens that persisted for more than 6 months. Twelve of 17 vaccinated patients (71%; 90% confidence interval, 52 to 89%) remain alive without recurrence at a median follow-up of 57 months. The results demonstrate that personalized vaccination of AML patients in remission induces the expansion of leukemia-specific T cells and may be protective against disease relapse.

Background A small, but immunogenic dose of red blood cells (RBCs) may be contained in apheresis platelets (PLTs). Attempts are made to provide D− recipients with D− PLTs to prevent anti-D alloimmunization and the potential for hemolytic disease of the fetus and newborn. Beth Israel Deaconess Medical Center has a policy that when necessary to transfuse D+ PLTs to D− patients, we recommend that RhIG be given when the patient is a woman of child-bearing age or a potential liver transplant patient. We sought to retrospectively determine the rate of anti-D formation after D-incompatible apheresis PLT transfusions in those patients not receiving RhIG and not receiving D+ RBCs over a 14-year period at our institution. Study Design and Methods All D− patients (626) who received D+ prestorage leukoreduced apheresis PLTs between January 1, 1997, and December 31, 2011, were identified. Those patients who received RhIG (45), D+ RBC transfusions (50), or stem cell transplantation from a D+ donor (16); had prior anti-D (23); or had unresolved Rh at admission (8) were not eligible for analysis. Only those patients who had an antibody screen performed at least 4 weeks after the incipient PLT transfusion were evaluated (130). Results Of 130 eligible D− patients, 48% women and 57% immunocompetent, who received a total of 565 apheresis PLTs, none formed anti-D. Conclusion These findings support the use of D+ apheresis PLTs without RhIG irrespective of D status in all recipients.

Purpose: A multiple myeloma vaccine has been developed whereby patient-derived tumor cells are fused with autologous dendritic cells, creating a hybridoma that stimulates a broad antitumor response. We report on the results of a phase II trial in which patients underwent vaccination following autologous stem cell transplantation (ASCT) to target minimal residual disease. Experimental Design: Twenty-four patients received serial vaccinations with dendritic cell/myeloma fusion cells following posttransplant hematopoietic recovery. A second cohort of 12 patients received a pretransplant vaccine followed by posttransplant vaccinations. Dendritic cells generated from adherent mononuclear cells cultured with granulocyte macrophage colony-stimulating factor, interleukin-4, and TNF-α were fused with autologous bone marrow–derived myeloma fusion cells using polyethylene glycol. Fusion cells were quantified by determining the percentage of cells that coexpress dendritic cell and myeloma fusion antigens. Results: The posttransplant period was associated with reduction in general measures of cellular immunity; however, an increase in CD4 and CD8+ myeloma-specific T cells was observed after ASCT that was significantly expanded following posttransplant vaccination. Seventy-eight percent of patients achieved a best response of complete response (CR)+very good partial response (VGPR) and 47% achieved a CR/near CR (nCR). Remarkably, 24% of patients who achieved a partial response following transplant were converted to CR/nCR after vaccination and at more than 3 months posttransplant, consistent with a vaccine-mediated effect on residual disease. Conclusions: The posttransplant period for patients with multiple myeloma provides a unique platform for cellular immunotherapy in which vaccination with dendritic cell/myeloma fusion fusions resulted in the marked expansion of myeloma-specific T cells and cytoreduction of minimal residual disease. Clin Cancer Res; 19(13); 3640–8. ©2013 AACR.

Therapeutic plasma exchange (TPE) is a proven treatment for thrombotic thrombocytopenic purpura (TTP) characterized by severe ADAMTS13 deficiency, but the efficacy of TPE in suspected TTP with an ADAMTS13 activity level of more than 10% remains controversial.We conducted a propensity score (PS)-matched study of 186 adult patients included in the Harvard Thrombotic Microangiopathy (TMA) Research Collaborative registry who presented with TMA suggestive of TTP but an ADAMTS13 activity level of more than 10%.Before matching, patients treated with TPE (n = 71) differed from untreated patients (n = 115) by several clinical measures. PS matching was performed to address clinical disparities between the two groups and resulted in a well-balanced cohort of 59 TPE-treated patients paired with 59 untreated controls, all of whom had TMA. After matching, we observed no significant difference in the primary outcome of 90-day survival between the treated and untreated groups (hazard ratio, 0.88; 95% confidence interval [CI], 0.44-1.77; p = 0.72). In-hospital mortality (odds ratio [OR], 0.77; 95% CI, 0.34-1.75; p = 0.53) and the percentage of patients with platelet count recovery (OR, 1.58; 95% CI, 0.77-3.26; p = 0.21) also did not differ significantly between the two matched groups.Our data suggest that routine use of TPE in the diverse group of TMA patients without severe ADAMTS13 deficiency may not significantly improve outcomes.

B lood transfusion continues to be an everincreasing activity within the medical community; recent survey data shows an approximate 6% increase in red blood cell (RBC) transfusions, 12% increase in plasma transfusions, and 20% increase in platelet (PLT) transfusions between 2006 and 2008 equating to approximately 21 million blood products being transfused annually. Moreover, the financial burden of blood at many institutions is significant; for instance, at our institution, an academic tertiary medical center, blood acquisition costs comprise approximately 35% of the annual supply budget for the Department of Pathology. Given the prominence of blood transfusion in the practice of clinical medicine, the importance of transfusion and blood safety, and the continued escalation of health care costs, assessment of blood utilization practice is an important aspect of institutional quality and safety programs and is endorsed by the Joint Commission and the Center for Medicare Services. AABB Standard 8.2 also requires this review and lists 10 areas that should be monitored. Two of these areas are “appropriateness of use” and “compliance with peer review recommendations.” Aside from these mandates, there is relatively little guidance on the mechanics of blood component utilization review. The AABB technical guidance document, published in 2001, describes general approaches to utilization audits (i.e., prospective, concurrent, and retrospective) as well as suggestions for thresholds for evaluating the appropriateness of transfusions (e.g., “PLT count < 50 ¥ 10/L and impending surgery”). There are benefits and shortcomings of the various approaches to utilization review. Under ideal circumstances, prospective review of blood product orders for both appropriateness of product selection and timing of administration offers the best opportunity to avoid unnecessary transfusion. However, the prospective review of all blood product requests is labor-intensive and risks, in urgent situations, delay of optimal patient care delivery. A concurrent review process involves review of blood component use within hours to 1 to 2 days after the transfusion episode. The advantage to this approach is that the reviewer can obtain all pertinent laboratory and clinical data surrounding the transfusion event and make a judgment as to the appropriateness of blood component use. If the transfusion episode appears to be out of line with good clinical practice, the reviewer has the opportunity to interact with the clinician who, based on the proximity to the event, will more than likely still be caring for the patient. Retrospective review is, without a doubt, the easiest approach to utilization review. With this approach, transfusion episodes can be assessed using preset review criteria. Cases that fall outside of these criteria can be evaluated more closely to determine whether or not extenuating clinical circumstances justified the request for blood products. The disadvantage of this approach is that the opportunity for effective intervention is lost since the ordering physician is likely no longer involved with the patient (particularly when the transfusion event occurs in an acute care setting) nor likely to recall the specifics of the event triggering the request for blood component transfusion. While recognizing the pros and cons to the various approaches to utilization review is important, the AABB technical guidance document does not delve into operational specifics of creating an audit program because “each transfusion committee . . . is responsible for developing its own blood utilization procedures and audit criteria.” In this article, we provide more direct “how to” information by describing our system for auditing blood product utilization.

We have developed a tumor vaccine in which patient-derived myeloma cells are chemically fused with autologous dendritic cells (DCs) such that a broad spectrum of myeloma-associated antigens are presented in the context of DC-mediated costimulation. We have completed a phase 1 study in which patients with multiple myeloma underwent serial vaccination with the DC/multiple myeloma fusions in conjunction with granulocyte-macrophage colony-stimulating factor. DCs were generated from adherent mononuclear cells cultured with granulocyte-macrophage colony-stimulating factor, interleukin-4, and tumor necrosis factor-α and fused with myeloma cells obtained from marrow aspirates. Vaccine generation was successful in 17 of 18 patients. Successive cohorts were treated with 1 × 106, 2 × 106, and 4 × 106 fusion cells, respectively, with 10 patients treated at the highest dose level. Vaccination was well tolerated, without evidence of dose-limiting toxicity. Vaccination resulted in the expansion of circulating CD4 and CD8 lymphocytes reactive with autologous myeloma cells in 11 of 15 evaluable patients. Humoral responses were documented by SEREX (Serologic Analysis of Recombinant cDNA Expression Libraries) analysis. A majority of patients with advanced disease demonstrated disease stabilization, with 3 patients showing ongoing stable disease at 12, 25, and 41 months, respectively. Vaccination with DC/multiple myeloma fusions was feasible and well tolerated and resulted in antitumor immune responses and disease stabilization in a majority of patients.

SummaryIt was the purpose of the present study to validate administrative claims codes for idiopathic thrombotic thrombocytopenic purpura (TTP) in a commercially-insured US population. Patients with at least one medical claim with ICD-9 code 446.6X between 1/1/2001 and 5/31/2008 were identified in the HealthCore Integrated Research Database™ (HIRD). A chart abstraction form was developed to enable case determination for patients identified by the claims code. Two clinical experts, not involved in the design of the study, reviewed the abstracted medical record data and determined whether definite evidence supporting the diagnosis of TTP was present. The positive predictive value (PPV) of the claims coding algorithm for cases assessed by both reviewers was computed. The claims algorithm was further refined and the PPV of the refined algorithm was computed. One hundred eighty-nine abstracted charts were reviewed by two clinical experts; 86 were assessed to have definite evidence supporting the diagnosis of TTP (PPV 45.5% [86/189; 95% confidence interval (CI), 38.3–52.9%]). Refinement of the claims algorithm first included the use of plasma exchange treatment, resulting in 103 potential cases, of which 67 were assessed to have definite evidence supporting the diagnosis of TTP (PPV 65.0%; 95% CI, 55.0–74.2%). Further refinement of the claims algorithm ruled out alternative diagnoses that may mimic TTP; 34 were assessed to have definite evidence supporting the diagnosis of TTP (PPV 72.3% [34/47; 95% CI, 57.4–84.4%]).Our findings demonstrate the difficulty of confirming the diagnosis of rare disorders that lack definite diagnostic criteria, and indicate that more complex claims coding algorithms are necessary for identifying these disorders.

Background: Non-ABO alloantibodies are frequently implicated in hemolytic transfusion reactions and are a leading cause of transfusion-related mortality. Detection of clinically significant non-ABO alloantibodies is reliant on an antibody screen, which is prone to clerical, technical, and reagent error. Data on the frequency of false-negative antibody screens due to the occurrence of these errors are scarce, and the true incidence of false-negative antibody screens in everyday practice is unknown. STUDY DESIGN AND METHODS: Monitoring for false-negative antibody screens is routinely performed in our institution. All cases of false-negative antibody screens involving clinically significant antibodies were identified through review of the blood bank quality assurance records from 2004 to 2007. The clinical impact was recorded in each case. RESULTS: Twenty-one cases of false-negative antibody screens due to clinically significant antibodies were detected. Sources of error included testing error (12 cases), reagent red blood cell (RBC) failure (one case), and reagent limitations (one case). The cause of error was inconclusive in seven cases. Nine patients were found to have received antigen-incompatible blood as a consequence of these errors, resulting in a single nonfatal hemolytic transfusion reaction. CONCLUSIONS: The identification and investigation of false-negative antibody screens is a valuable quality assurance measure which can serve to monitor staff performance, identify cases of reagent RBC failure, and identify patients who have received antigen-incompatible blood at risk for hemolytic transfusion reactions.

Phlebotomy errors leading to incompatible transfusions are a leading cause of transfusion-related morbidity and mortality. Our institution's specimen-labeling policy requires the collection date, 2 unique patient identifiers, and the ability to identify the phlebotomist. This policy, however, was initially strictly enforced only by the blood bank. In fiscal year 2005, following an educational campaign on proper specimen labeling, all clinical laboratories began strictly adhering to the specimen-labeling policy. Compared with the preceding 4 years, in the 3 years following policy implementation, the incidence of wrong blood in tube (WBIT) and mislabeled specimens detected by the blood bank decreased by 73.5% (0.034% to 0.009%; Por = .0001) and by 84.6% (0.026% to 0.004%; Por = .0001), respectively. During a short period, a simple, low-cost educational initiative and policy change can lead to statistically significant decreases in WBIT and mislabeled specimens received by the blood bank.

BACKGROUND: Immune thrombocytopenic purpura and secondary thrombocytopenia patients treated with Rho(D) immune globulin intravenous (human; anti-D IGIV) have experienced acute hemolysis, which is inconsistent with the typical presentation of extravascular hemolysis—the presumed mechanism of action of anti-D IGIV. Although the mechanism of anti-D-IGIV–associated acute hemolysis has not been established, the onset, signs/symptoms, and complications appear consistent with the intravascular hemolysis of acute hemolytic transfusion reactions (AHTRs). In transfusion medicine, the red blood cell (RBC) antigen-antibody incompatibility(-ies) that precipitate AHTRs can be detected in vitro with compatibility testing. Under the premise that anti-D-IGIV–associated acute hemolysis results from RBC antigen-antibody–mediated complement activation, this study evaluated whether the incompatibility(-ies) could be detected in vitro with a hemolysin assay, which would support the AHTR model as the hemolytic mechanism. STUDY DESIGN AND METHODS: Seven anti-D IGIV lots were tested to determine the RBC antibody identities in those lots, including four lots that had been implicated in acute hemolytic episodes. Hemolysin assays were performed that tested each of 73 RBC specimens against each lot, including the RBCs of one patient who had experienced acute hemolysis after anti-D IGIV administration. RESULTS: Only two anti-D IGIV lots contained RBC antibodies beyond those expected. No hemolysis endpoint was observed in any of the hemolysin assays. CONCLUSION: Although the findings did not support the AHTR model, the results are reported to contribute knowledge about the mechanism of anti-D-IGIV–associated acute hemolysis and to prompt continued investigation into cause(s), prediction, and prevention of this potentially serious adverse event.

Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin therapy. Limited data are available regarding repeat HIT antibody testing after an initial negative test. We conducted a retrospective study to determine the utility of repeat testing. Heparin antibodies were detected using the GTI-PF4 enzyme-linked immunoabsorbent assay, ELISA (GTI Diagnostics, Waukesha, WI). Patients (n = 137) were assigned to one of three groups based upon the initial negative test optical density (OD) range of low = 0-0.132, medium = 0.133-0.267, and high = 0.268-0.399. A pretest clinical score was retrospectively determined using the "4T's" (Thrombocytopenia, Timing of platelet fall, Thrombosis, and the absence of oTher causes of thrombocytopenia). A subsequent positive ELISA was found in 16% (22/137) of patients who underwent repeat testing. Most of these patients had a low pretest clinical score (62%). Four patients had an interval change in the pretest score between the initial negative and subsequent positive tests. Only these four patients developed HIT with thrombosis (HITT). Eighty percent of patients with a high initial negative test OD value had a positive ELISA on repeat testing; however, the initial negative test OD value could not predict whether a patient developed HITT. In contrast, an increase in the pretest clinical probability between initial and repeat testing better predicted HITT. Consecutive repeat ELISA testing for heparin antibodies may be warranted in patients with an increase in their pretest clinical score after an initial negative test as an adjunct to confirm the diagnosis of HIT.

BACKGROUND: To improve donor management for donor lymphocyte collections, a protocol was established to tailor the amount of whole blood processed during leukapheresis to achieve the requested cellular dose. STUDY DESIGN AND METHODS: A retrospective review of donor and product records of all donors who provided donor lymphocytes during the period October 27, 1999, to March 2, 2005, was performed (25 donors, 54 collections). Data on product total CD3+ T cells collected and total blood volume (TBV) processed were used to establish a correlation between the two variables. The resultant correlation from the reference group (8 donors, 13 collections) was then used to prospectively determine the TBV to be processed in a subsequent series of collections (“prospective group”: 18 donors, 41 collections). Donor charts were also reviewed to determine leukapheresis-associated adverse events. RESULTS: The application of the correlation data between TBV processed and CD3+ T-cell yields from the initial reference group to the prospective group yielded 92 percent successful collections; in 3 of the 4 inadequate collections, the predefined maximum of three times their TBV was processed. Compared to the reference group, the TBV processed in the prospective group was decreased from 12,598 ± 4007 to 7942 ± 5079 mL; the length of procedure was decreased from 208 ± 53 to 146 ± 79 minutes. Adverse event data were reviewed for 51 collections; the percentage of procedures without adverse events increased from 23 percent in the reference group to 37 percent in the prospective group. CONCLUSION: Application of correlation data between TBV processed and CD3+ T-cell yield was useful to predict efficient and successful donor lymphocyte collections.

BACKGROUND: Recombinant activated factor VII (rFVIIa) is being tested to improve hemostasis in a variety of bleeding disorders. Clinical indications and efficacy are still being evaluated for this product. CASE REPORT: Over a 17-month period, rFVIIa was used to treat central nervous system hemorrhage in three patients who were found to have isolated FVII deficiency (21%, 40%, 27%). Patient A fell 30 feet, Patient B suffered a motor vehicle accident, and Patient C had a spinal cord hematoma. None of the patients had a history of bleeding diathesis. All three patients received rFVIIa after failing initial treatment with fresh-frozen plasma. RESULTS: Patient A was treated with 11 doses (initial dose 95 µg/kg; subsequent doses 8-38 µg/kg) over 10 days; Patient B received 13 doses (45-60 µg/kg) over 13 days; and Patient C received 5 doses (12-24 µg/kg) over 4 days. The prothrombin time corrected from 16.2 ± 1.8 (mean ± SD) to 11.2 ± 1.6 seconds after infusion of rFVIIa, but returned to pretreatment level in 14 ± 4 hours. At the cessation of therapy, all patients showed neurologic improvement. No complications related to the infusion of rFVIIa occurred. CONCLUSION: The use of rFVIIa may be of value both for its general effect on hemostasis, and specifically in the setting where there is a documented reduction in FVII. Doses lower than those used in patients with FVIII inhibitors appear to be effective in the setting of central nervous sytem hemorrhage.