American Association of Blood Banks

Abstract Rationale: Systemic corticosteroids are standard-of-care treatment for asthma exacerbations; however, little is known about whether corticosteroid effects on airway inflammatory pathways differ when added to biologic therapies targeting type 2 inflammation. Methods: 290 urban children (6-17 years) with exacerbation-prone eosinophilic asthma were randomized (1:1) to q4 week placebo or mepolizumab injections added to guideline-based care for 52 weeks. Nasal lavage samples were collected at baseline (before treatment), post-exacerbation (5-10 days after starting systemic corticosteroids), and on treatment for RNA-sequencing. Differentially expressed genes (DEGs) were assessed using mixed effects modeling (significance threshold FDR<0.05). Results: 98 participants were evaluated following 170 exacerbation events (placebo:105, mepolizumab:65). In the placebo group, there were no significant differentially expressed genes comparing on treatment to before treatment timepoints. In the placebo group, there were 6363 significant DEGs (2734 increased, 3629 decreased) comparing post-exacerbation to on treatment. In the mepolizumab group, there were 1404 significant DEGs (664 increased, 740 decreased) comparing on treatment to before treatment (Fig1A: x-axis). In the mepolizumab group, there were 1111 significant DEGs (413 increased, 698 decreased) comparing post-exacerbation to on treatment (Figure 1A: y-axis). In the post-exacerbation versus on treatment contrasts, there were 885 overlapping significant DEGs (348 increased, 537 decreased) between the placebo and mepolizumab participants. Mepolizumab reduced expression of eosinophil-associated genes (CCL23, GATA1, CLC, PRSS33, PTGDR2, ADORA3, THBS4) on treatment, with a larger decrease post-corticosteroid (more reduced than placebo) (FDR<0.05) (Fig1B). Mepolizumab did not significantly alter expression of mast cell/T2 cytokine-related genes (HDC, CPA3, GATA2, TPSAB2, IL5, IL13, IL1RL1, ALOX15) on treatment; however, expression of these genes significantly decreased post-corticosteroid (more reduced than placebo) (FDR<0.05) (Fig1B). Mepolizumab increased expression of genes associated with epithelial and airway inflammation (CFTR, ERBB2, BMP3, TRPV4) on treatment; however, expression of these genes returned to baseline levels post-corticosteroid (FDR<0.05) (Fig1B). Conclusions: By comparing differential gene expression across treatment groups and time points, we identified overlapping DEGs related to systemic corticosteroid effects, DEGs related only to mepolizumab treatment, and clusters of functionally related genes with additive effects of mepolizumab plus systemic corticosteroids. Mepolizumab enhances the actions of oral corticosteroids on eosinophil related pathways in relation to exacerbations. Oral corticosteroids provide the added benefit of down-regulating mast cell and T2 cytokine pathways. Finally, oral corticosteroids reverse the up-regulation of epithelial inflammatory pathways that occurred during mepolizumab treatment.

Abstract Randomized controlled trials (RCTs) are the gold standard for evaluating drug safety and efficacy in controlled settings, but they have limited generalizability due to their focus on selective and homogeneous populations. Real-world-data (RWD), collected from larger and more varied patient populations, can address inherent limitations of RCTs and aid in clinical trial design and drug approval. However, with the challenges of RWD, unlocking its full potential for tumor target and biomarker identification and validation demands innovative analytical approaches. Here we present RWD analyses of ConcertAI® electronic health records (EHR) linked with Caris Lab data for 2,659 lung cancer patients. Comprehensive genomics analyses incorporate WES and RNA-seq data, coupled with rich clinical EHR data. By integrating clinical and genomics data, we showcase the potential of harnessing RWD as follows: (1) we investigated genomic alterations across five histology groups (adenocarcinoma, squamous, large cell, small cell lung cancer [SCLC], neuroendocrine [NE] lung cancer). Notably, TP53 and LRP1B mutations were prevalent across all groups. LRP1B mutations correlated with higher tumor mutation burden, indicative of a favorable response to immunotherapy. Biallelic TP53 and RB1 inactivation was predominant in SCLC and NE lung tumors. The five histological groups exhibit distinct expression profiles, reflecting tumor intrinsic characteristics. Most immune gene signature scores were significantly lower in SCLC and NE tumors, aligned with that they are cold tumors with immune resistance, except CD56-centered NK and neuroendocrine gene signatures; (2) we analyzed patient treatment patterns and persistence by line of therapy. Among the 206 NSCLC patients with clinically actionable EGFR mutations, 143 received targeted therapy during their treatment courses (69.4%). Time to treatment discontinuation (TTD) was used as a surrogate clinical outcome endpoint. TTD was significantly longer when TKI was the first line treatment compared to later lines (p = 0.01), while the trend is opposite for ICI where TTD is significantly shorter in the 1st line setting (p = 0.025); (3) we highlight the unique potential of leveraging H&E imaging modality in such RWD. In summary, we successfully identified unique molecular signatures among various lung cancer histological groups, pinpointed distinct subpopulations within lung adenocarcinoma and squamous tumors linked to their immune phenotypes, and investigated the different patient treatment patterns and outcomes, facilitating personalized medicine. In the broader context of our work, we have developed a framework for harnessing various data modalities (clinical, multi-omics, imaging) within AbbVie's oncology RWD realm, enhancing the discovery and validation of new oncology targets and biomarkers. Citation Format: Si Wu, Weilong Zhao, Christy Choi, Mona Cai, Peter Ansell, Alexander Liede, Rong Chen, Xi Zhao, Josue Samayoa. Harness the power of real-world-data for oncology target and biomarker research: A case study by applying clinic-genomics data for 2,659 lung cancer patients and beyond [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2551.

To assess patient blood management (PBM) practices across the globe, the Association for the Advancement of Blood and Biotherapies (AABB) conducted a survey on PBM in 2022 which was unique due to its transcontinental outreach and served as a worldwide snapshot of the prevalent practices. AABB's Transfusion Safety/PBM subsection formed a workgroup to construct the survey and obtain data for 2021 conducted from May 31, 2022 through June 15, 2022. It was distributed to global AABB hospital members and non-AABB members. As a subset analysis, the North American (NA) responses were compared with the results from AABB's 2013 Blood Survey. Responses were received from 274 facilities including 69 non-NA member responses across 5 WHO regions as compared to 14 non-US member responses in 2013. Globally, 126/274 (45.9%) respondents reported having a PBM program vs NA cohort (2022) 103/205 (50.2%) versus 207/555 (37.3%) in 2013. Globally, the PBM programs involved pathologists 71 (56.3%), blood bank supervisor/managers 53 (42.1%) and transfusion medicine consultants 26(21.1%) with pathologists 70/103 (67.9%) highest in the NA cohort. Globally, transfusion thresholds were derived from AABB 205/267 (76.8%), College of American Pathologists 111/267 (41.6%) and hospital-developed guidelines 119 (44.6%) used individually or combined. In the NA cohort, AABB was used by 91/103 (88.3%). Out of the 206/274 (75.1%) who reported the usage of alternates to blood products, the majority used vitamin K 188(91.2%), tranexamic acid 167 (81.1%), and fibrin sealant 85 (41.2%). In the NA cohort, 151/205 (73.6%) reported similar distribution. Blood is not an option programs (BNAO) were available at 110/273 (40.3%) of respondents' facilities with the NA cohort having similar results 86/204 (41.9%). Globally, 60/272 (22.1%) had a formal service to manage the patient's anemia, in the NA cohort (2022) 41/204 (20.0%) versus 36/87 (41.4%) in 2013. Regarding the promotion of single-unit transfusions, this was reported globally by 101/126 (80.2%) versus NA cohort (2022) 86/205 (41.9%) versus 27/55(52.0%) in 2013. Formal PBM training and education was conducted globally at 62/126 (49.2%) centers versus NA cohort (2022) 47/103(45.6%) versus 366/555 (65.9%) in 2013. This global PBM survey captured more facilities outside of the NA than in 2013. The percentage of PBM programs reported has increased since the last survey, however, it is still in a minority of hospitals outside of NA. The majority have implemented transfusion thresholds based upon professional association recommendations and promote single-unit red blood cell transfusions. Areas of improvement (response <50%) include BNAO programs, anemia management and educational programs which have decreased since the last survey. This survey tells us where we are today and may serve as our roadmap ahead.

Mass casualty incidents (MCIs) create an immediate surge in blood product demand. We hypothesize local inventories in major U.S. cities would not meet this demand. A simulated blast in a large crowd estimated casualty numbers. Ideal resuscitation was defined as equal amounts of red blood cells (RBCs), plasma, platelets, and cryoprecipitate. Inventory was prospectively collected from six major U.S. cities at six time points between January and July 2019. City-wide blood inventories were classified as READY (>1 U/injured survivor), DEFICIENT (<10 U/severely injured survivor), or RISK (between READY and DEFICIENT), before and after resupply from local distribution centers (DC), and features of DEFICIENT cities were identified. The simulated blast resulted in 2218 injured survivors including 95 with severe injuries. Balanced resuscitation would require between 950 and 2218 units each RBC, plasma, platelets and cryoprecipitate. Inventories in 88 hospitals/health systems and 10 DCs were assessed. Of 36 city-wide surveys, RISK inventories included RBCs (n=16; 44%), plasma (n=24; 67%), platelets (n=6; 17%), and cryoprecipitate (n=22; 61%) while DEFICIENT inventories included platelets (n=30; 83%) and cryoprecipitate (n=12; 33%). Resupply shifted most RBC and plasma inventories to READY, but some platelet and cryoprecipitate inventories remained at RISK (n=24; 67% and n=12; 33%, respectively) or even DEFICIENT (n=11; 31% and n=6; 17%, respectively). Cities with DEFICIENT inventories were smaller (p <.001) with fewer blood products per trauma bed (p <.001). In this simulated blast event, blood product demand exceeded local supply in some major U.S. cities. Options for closing this gap should be explored to optimize resuscitation during MCIs.

Abstract Blood group antigens are the archetypal example of human genetic variation. Here, we characterised the functional metabolic consequences in individuals homozygous for a 17bp deletion in SMIM1 (rs566629828; minor allele frequency 0.0147) and thus lacking the protein defining the Vel blood group. Our analysis, in separate cohorts of SMIM1-/- individuals (UK Biobank, NHS Blood and Transplant, Danish Blood Donor Study, Copenhagen Hospital Biobank) and a mouse model, identified an increase in body weight accompanied by a range of metabolic differences, including dyslipidemia, changes in the leptin-adiponectin ratio, increased liver enzymes and lower total thyroid hormone levels. These changes in the metabolic state were at least in part due to a reduction in resting energy expenditure, as assessed during an in-depth clinical assessment of SMIM1-/- individuals. Additionally, electronic health records suggest that individuals lacking this 78-amino-acid type II transmembrane protein may be more prone to cerebral bleeds and thrombotic stroke.