Background Patients with sickle cell disease (SCD) are frequent recipients of red blood cell (RBC) transfusions and are at risk for RBC alloimmunization. RBC alloimmunization is diagnosed by identifying RBC alloantibodies as part of pre‐transfusion testing, but this testing fails to detect alloantibodies that have evanesced. It may be beneficial to screen for new RBC alloantibody development after transfusion before possible antibody evanescence. Study Design and Methods Our institution started a new initiative for episodically transfused patients with SCD to obtain at least one antibody screen 2–6 months after transfusion as part of their clinical care. A database was created to prospectively track all transfused patients for 1 year and their post‐transfusion antibody screen results. Patients received prophylactically CEK‐matched RBC units. Results During the study year, 138 patients with SCD received a total of 242 RBC transfusions. Patients with a history of an RBC alloantibody (n = 13, 9.4%) had previously received more RBC units than non alloimmunized patients (median 11 vs. 2 RBC units, p = .0002). A total of 337 post‐transfusion antibody screens were obtained in 127 patients (92.0%) with 110 patients (79.7%) having at least one antibody screen 2–6 months post‐transfusion. With this prospective testing, two new RBC alloantibodies (anti‐C and ‐M) were identified in two patients. Conclusion It is feasible to test for new RBC alloantibody development in most episodically transfused patients with SCD as part of their routine care. The yield of this screening appears low with CEK matching, but it could still provide important information for individual patients.

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BACKGROUND Noonan syndrome (NS) is one of several autosomal dominant multisystem disorders known as RASopathies. Common manifestations of NS include congenital heart defects and cardiomyopathy, lymphatic malformations, and predisposition to myeloproliferative disorders. Chylous fluid accumulation secondary to lymphatic malformations are seen in NS and are a major cause of morbidity and mortality often refractory to conventional medical management. There has been increasing interest in the use of pharmacologic MEK inhibition in the management of these patients given that activating RAS pathway mutations lead to downstream MEK activation that is causative of this pathology. DESIGN/METHODS Three patients with a confirmed diagnosis of NS are described. Each patient developed complications from chylous effusions refractory to conventional management and were subsequently enrolled on-study to treat with compassionate use oral trametinib from Novartis Pharmaceuticals on a single patient Investigational New Drug from the Food and Drug Administration (FDA). All patients were consented to be monitored for one year of therapy following a local protocol approved by the Colorado Institutional Review Board (COMIRB). Patient 1: a 4-year-old female with NS due to a pathogenic germline mutation of the RIT1 gene [c.246T>G, p.Phe82Leu] born with severe hypertrophic cardiomyopathy, mitral valve dysplasia, and pulmonary valve stenosis. She developed bilateral chylous pleural effusions that were refractory to dietary modification, diuretics, octreotide, and sirolimus. Patient 2: a 3-month-old female with NS due to a pathogenic germline mutation of the SOS1 gene [c.1322G>A; p.Cys441Tyr] born with esophageal atresia/tracheoesophageal fistula and moderate pulmonary valve stenosis. She developed bilateral chylous pleural effusions and ascites that were refractory to dietary modification and octreotide therapy. Patient 3: a 4-month-old male with NS due to a gain-of-function mutation of PTPN11 [c.854T>C; p.Phe285Ser] with hypertrophic cardiomyopathy, pulmonary valve stenosis, respiratory insufficiency with suspected pulmonary lymphangiectasia, and persistent chylous pleural effusions in addition to Noonan syndrome-associated myeloproliferative disorder (NS-MPD) that had been refractory to traditional management. RESULTS MEK inhibition with trametinib was used in three patients with NS and life-threatening complications with no medical or surgical treatment options. All three patients had dynamic contrast magnetic resonance lymphangiography (DCMRL) evidence of primary, central lymphatic dysplasia that manifested in lymphatic accumulation affecting cardiorespiratory function, nutrition, and the immune system. DCMRL imaging for patient 2 are highlighted in Figure 1 A and B. Within one month of initiating trametinib oral therapy, all three patients demonstrated response adequate to wean from mechanical ventilation and other supportive care modalities. Serum albumin levels improved as lymphatic leak resolved (Figure 1C). Patient 3 showed improvement in hypertrophic cardiomyopathy as evidenced by a decrease in both NT-proBNP and left ventricular mass by echocardiogram. Patients 1 and 2 demonstrated notable improvements in growth after one year of therapy, with increase in both weight and height percentiles. Patient 3 also presented with NS-MPD that responded with marked improvements in total WBC count as well as absolute monocyte count (Figure 1D). DISCUSSION Our experience adds to the growing body of evidence demonstrating the effectiveness of MEK inhibition on disease processes that are common in patients with NS and other RASopathies. None of the patients in our series experienced significant adverse effects from the medication aside from patient 2 who developed mild dermatitis. The efficacy of this therapy does not appear to be based on the underlying genotype, as each of the three patients we describe had different underlying molecular alterations (SOS1, RIT1, PTPN11). Substantial improvements in a variety of parameters including lymphatic malformations, cardiomyopathy, pulmonary valve stenosis, growth, and NS-MPD highlight the potential utility of trametinib in this patient population. Larger, prospective studies are necessary to confirm the efficacy of MEK inhibition and to assess the long-term safety of its use in this population. Figure 1 Figure 1. Disclosures Nakano: Novartis: Consultancy. OffLabel Disclosure: Trametinib is a MEK1/2 inhibitor that has been approved for the use in certain malignancies. Its off label use in children with Noonan Syndrome with significant lymphatic anomalies is based on the up regulation of the MAPK pathway in these patients.

BACKGROUND Pediatric immune thrombocytopenia (ITP) is an acquired disorder of platelet destruction that is associated with an increased risk of bleeding. Despite published guidelines for the management of ITP, the available evidence is of low grade, leading to practice variation in different settings. The use of validated bleeding scores to guide clinical decision making is inconsistent. In addition, many children are initially treated with medications despite the recommendation for observation in newly diagnosed children with ITP and no or mild bleeding symptoms. This approach leads to over-utilization of healthcare resources including hospitalizations, medication administration, and medical encounters for management-related side effects. In 2020, a quality improvement (QI) project of the Pediatric ITP Consortium of North America (ICON) was initiated to improve consistency in clinical practice at ICON sites using national ITP guidelines. DESIGN/METHODS Within the ICON QI subcommittee, a standardized clinical care pathway (Figure 1) for newly diagnosed childhood ITP was developed based on the American Society of Hematology (ASH) 2019 guidelines. The goal was to unify approach to management, decrease practice variation, identify and learn from deviations in decision making, and decrease resource utilization by increasing observation rates in low-risk pediatric ITP patients. Site investigators shared the care pathway to update institutional providers on national guidelines. For Aim 1 of this project, sites completed a multi-center, retrospective analysis documenting the pre-QI pathway management of children, ages 1-16 years, diagnosed with ITP from January to December 2019. Statistical analysis was performed using R version 4.0.2. For Aim 2, after local dissemination and education of the clinical care pathway, clinicians at all participating sites will review the pathway at the time of managing newly diagnosed children and then complete a short survey documenting a bleeding score and management decisions. RESULTS Current data from the retrospective review is summarized in Figure 1. 98 patients across four ICON institutions are included in this analysis. The median age at diagnosis was 6 years (IQR 2.7, 9.2) with 61% being male. 43 (44%) patients had their first hematology encounter in the inpatient setting, 40 (41%) in the outpatient clinic, and 14 (14%) in the emergency room. Buchanan and Adix bleeding scores were obtained from only one patient (1%) at diagnosis. Treatment strategies varied including observation in 47 (48%) patients, IVIG in 40 (41%), corticosteroids in 9 (9%), and anti-D globulin in 3 (3%). 53 (54%) patients were admitted at the time of diagnosis. The prospective QI pathway is being utilized by six ICON institutions and 20 patients have been followed on the pathway since November 2020. An additional seven sites are in various phases of study activation. DISCUSSION Evidence-based ITP guidelines and an expert consensus report have been recently published. For children with newly diagnosed ITP and a platelet count <20 x 10 9/L who have no or mild bleeding, ASH guidelines suggest against admission to the hospital and suggest observation rather than treatment with corticosteroids. Retrospective analysis of the management at four ICON centers demonstrates the variation in approach to treatment. However, although guidelines suggest initial management based on objective assessment of bleeding symptoms, only one patient (1%) had a documented bleeding score at presentation, suggesting a lack of a standard approach to management and practice variation. These data support the need for this quality initiative, which involves clinicians reviewing the pathway while managing patients and answering a survey at the time of clinical visits to report on bleeding symptoms and management. This initiative will be expanded to include a total of 13 institutions across the United States. Data will be analyzed every 1-2 years and changes will be made to the pathway with the goal of improving care. Further quality initiatives may help to standardize the management approach of pediatric ITP patients and optimize health outcomes in this patient population. Figure 1 Figure 1. Disclosures Badawy: Bluebird Bio Inc: Consultancy; Sanofi Genzyme: Consultancy; Vertex Pharmaceuticals Inc: Consultancy. Grace: Novartis: Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Research Funding; Principia: Membership on an entity's Board of Directors or advisory committees. Nakano: Novartis: Consultancy.

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Introduction: Red blood cell (RBC) transfusions are important in the management of patients with sickle cell disease (SCD). However, a potentially catastrophic complication of transfusion in this population is the delayed hemolytic transfusion reaction (DHTR). The pathophysiology of all DHTRs is not understood, but some are known to be caused by an anamnestic resurgence of RBC alloantibodies. Case presentation:A child with SCD transfused for acute chest syndrome re-presented a week after hospital discharge with severe anaemia, hemolysis, and a newly detected anti-E. This patient had been previously transfused years ago at an outside institution and the anti-E had not been previously documented.Discussion: The presented case of an antibody positive DHTR illustrates several concepts critical to the prevention of this complication. RBC alloantibodies must be detected and this information must be shared. Prophylactic C/c, E/e, K antigen matching is helpful for patients with SCD, but systems must be in place to identify these patients. Patients transfused at multiple different hospitals are especially at risk for this complication and efforts are needed to prevent them from suffering a DHTR.

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