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Background Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by anemia, short stature, congenital anomalies, and cancer predisposition. Most cases are due to mutations in genes encoding ribosomal proteins (RP) leading to RP haploinsufficiency. Effective treatments for the anemia of DBA include chronic red cell transfusions, long-term corticosteroid therapy, or hematopoietic stem cell transplantation. In a small patient series and in animal models, there have been hematologic responses to L-leucine with amelioration of anemia. The study objectives of this clinical trial were to determine feasibility, safety, and efficacy of L-leucine in transfusion-dependent patients with DBA. Procedure Patients ≥2 years of age received L-leucine 700 mg/m2 orally three times daily for nine months to determine a hematologic response and any improvement in growth (NCT01362595). Results This multicenter, phase I/II study enrolled 55 subjects; 43 were evaluable. There were 21 males; the median age at enrollment was 10.4 years (range, 2.5-46.1 years). No significant adverse events were attributable to L-leucine. Two subjects had a complete erythroid response and five had a partial response. Nine of 25, and 11 of 25, subjects experienced a positive weight and height percentile change, respectively, at the end of therapy. Conclusions L-leucine is safe, resulted in an erythroid response in 16% of subjects with DBA, and led to an increase in weight and linear growth velocity in 36% and 44% of evaluable subjects, respectively. Further studies will be critical to understand the role of L-leucine in the management of patients with DBA.

Background and objective Recurrent hospital admissions for patients with sickle cell disease (SCD) are costly and contribute to a low quality of life for patients. We implemented a clinical pathway to safely discharge SCD patients with fever who are evaluated in the emergency department (ED) of a large tertiary care center. Methods An interdisciplinary team of ED and hematology physicians, nurses, and an improvement advisor developed a clinical pathway that identified febrile SCD patients at low risk of serious bacterial infection based on historical, clinical, and laboratory criteria who could be discharged from the ED. Phone follow-up was planned through the use of an automated electronic notification that was sent to an established hematology follow-up pool at the time of ED discharge. We conducted two "fake front end" trials in the ED to receive feedback on our process before full implementation. A postpathway implementation quality improvement team monitored discharge rates, phone follow-up rates and adverse events. Results In the first 9 weeks postpathway implementation, 100 SCD patients were evaluated for fever; 84 (24%) met low-risk criteria and were discharged home. This reduction in admission rate has been maintained throughout the 3 years postimplementation. Successful phone follow-up was achieved in all discharged patients within 24 hours and no adverse events were identified. Conclusions Low-risk febrile patients with SCD can be safely discharged from the ED. An automated notification system within the electronic medical record system can facilitate patient follow-up after ED discharge. Future quality improvement efforts aimed to further reduce admissions in this population should target patients with modifiable risk factors for serious bacterial infection.

Background: Hydroxyurea (HU) is the primary medication used to prevent the significant medical and neurologic morbidities of pediatric sickle cell disease (SCD; HbSS or HbSB0 thalassemia). Despite the benefits of HU, it remains under-utilized likely due to lack of clinician knowledge/training and negative caregiver perceptions. Thus, we developed the Engage-HU randomized controlled trial (NCT03442114) as a novel approach to address HU utilization barriers. Engage-HU is designed to assess how clinicians can engage caregivers in a shared discussion that considers their values, preferences, and scientific evidence about HU. The COVID-19 pandemic has resulted in significant changes to healthcare delivery for children with SCD, as they are at increased risk of severe illness from COVID-19 infection. Given their risk status, it was recommended that patients with SCD complete telehealth visits when possible. Some families also chose to delay care because they feared their child would get infected at hospitals/healthcare clinics that care for COVID-19 positive patients. Since the lives of all families enrolled in the Engage-HU trial have been affected to some extent, we incorporated measures to capture the impact of the COVID-19 pandemic and the usability of telemedicine implementation and services. Methods: Engage-HU is a randomized control trial comparing two dissemination methods for clinicians to facilitate shared decision-making with caregivers of young children with SCD. Study outcomes include caregiver confidence in decision-making and perceptions of experiencing shared decision-making as well as HU uptake and child health outcomes. Eligible children are 0 to 5 years, candidates for HU, and their caregiver has not decided about HU in the past 3 months. The trial is being conducted at 9 sites in the United States and uses a unidirectional crossover design. The primary endpoints are caregiver decisional uncertainty and caregiver perception of shared decision-making measured using validated tools. Data will be analyzed using the intent-to-treat principle, and all participants will remain in the arm to which they were randomized. A multiple group comparison analysis will be performed to assess significant response variable differences by group randomization. The Engage-HU study aims to recruit 174 caregivers who are considering initiating HU. The trial is being conducted at 9 sites in the United States. Data collection is ongoing, and 160 caregiver-participants have been enrolled to date. Since May 2020, caregiver-participants have completed the COVID-19 Exposure and Family Impact Scales (CEFIS), which contain 2 subscales (exposure to potentially traumatic aspects of the pandemic, impact on families), and the COVID-19 telemedicine use survey during a study visit. Results: Currently, 8 of the 9 sites have collected data from 48 caregivers (93.8% mothers), most of whom (93.8%) identify as African American/Black (see Figure 1). Correlations indicated that older caregivers experienced greater exposure (Mean = 7.0, SD = 4.1, range = 1-19) to potentially traumatic aspects of the pandemic (r = .31, p = .04). Distress related to COVID-19 varied widely across the sample, for both caregivers (Mean = 5.9, SD = 2.9, range = 1-10) and children (Mean = 4.1, SD = 3.4, range = 1-10). Scores on the telemedicine usability survey were generally high, indicating that caregivers are happy with the quality of care delivered via telehealth. However, caregivers (r = .30, p = .09) and children (r = .32, p = .07) experiencing more pandemic-related distress reported less satisfaction with telehealth. Conclusion: Although Engage-HU has resumed research operations, recruitment has not reached pre-pandemic targets, as fewer eligible patients are scheduled for routine care visits at SCD clinics. Our preliminary analyses suggest a significant continued impact of the pandemic on families and general satisfaction with the quality of healthcare delivered via telemedicine. These findings indicate that targeted screenings to identify and intervene for those who demonstrate more COVID-19 pandemic-related distress are needed. Figure 1 Figure 1. Disclosures Quinn: Forma Therapeutics: Consultancy; Aruvant: Research Funding; Novo Nordisk: Consultancy; Emmaus Medical: Research Funding. Yates: Agios Pharmaceuticals: Current Employment. Badawy: Sanofi Genzyme: Consultancy; Vertex Pharmaceuticals Inc: Consultancy; Bluebird Bio Inc: Consultancy. Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Baxalta: Research Funding; Biomarin: Research Funding; Celgene/BMS: Consultancy, Research Funding; CRISPR Therapeutics: Research Funding; Vertex: Research Funding; Editas: Research Funding; Graphite Bio: Research Funding; Novartis: Research Funding; Agios: Consultancy; Beam: Consultancy; Global Blood Therapeutics: Current equity holder in publicly-traded company. Smith-Whitley: Global Blood Therapeutics: Current Employment. King: National Cancer Institute: Research Funding; National Heart, Lung, and Blood Institute: Research Funding; Health Resources and Services Administration: Research Funding; Global Blood Therapeutics: Research Funding. Meier: CVS Caremark: Consultancy; Forma Therapeutic: Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Membership on an entity's Board of Directors or advisory committees; Novartis,: Other: Data Safety Monitoring Board membership; NHLBI: Other: Data Safety Monitoring Board membership; Global Blood Therapeutics: Other: Steering Committee membership, grant funding; CDC,: Other: grant funding; Indiana Department of Health: Other: grant funding . Tubman: Global Blood Therapeutics: Consultancy, Research Funding; Novartis Pharmaceuticals: Honoraria, Research Funding; Forma Pharmaceuticals: Consultancy; Perkin Elmer: Honoraria. Crosby: Forma Therapeutics: Honoraria; PCORI: Research Funding; HRSA: Research Funding; Global Blood Therapeutics Panel: Honoraria; Children's Hospital of Philadelphia: Honoraria; Professional Resource Exchange: Patents & Royalties: $30-$60 every other year; SCDAA: Honoraria; NHLBI: Other: Payment for review of LRP Proposals, Research Funding. OffLabel Disclosure: Hydroxyurea has been FDA approved for the treatment of sickle cell disease for patients ages 2 years and above but NHLBI and ASH Guidelines recommend it be offered to children as young as age 9 months.

Fanconi anemia (FA), a genetic disorder affecting DNA repair, is characterized by bone marrow failure and cancer susceptibility. In FA mouse models, metformin (N,N-dimethylguanide) a biguanide metabolic agent, improves blood counts and delays tumor development. Given these findings, we conducted a single institution pilot study of metformin in non-diabetic patients with FA to assess feasibility, tolerability, and impact of metformin on hematologic response as defined by modified MDS International Working Group (IWG) criteria (Table 1). Fourteen of 15 patients with at least 1 cytopenia (hemoglobin Figure 1 Figure 1. Disclosures Pollard: Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees. Furutani: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Esrick: bluebird bio: Consultancy. Nakano: Novartis: Consultancy. Thompson: Celgene: Consultancy, Research Funding; bluebird bio: Consultancy, Research Funding; Biomarin: Research Funding; Vertex: Research Funding; Graphite Bio: Research Funding; Baxalta: Research Funding; CRISPR Therapeutics: Research Funding; Novartis: Research Funding; Agios Pharmaceuticals: Consultancy; Beam Therapeutics: Consultancy; Global Blood Therapeutics: Current equity holder in publicly-traded company. OffLabel Disclosure: metformin- use in Fanconi anemia in an effort to improve hematopoiesis

BACKGROUND Red blood cell (RBC) alloimmunization is a concern for patients who receive multiple or chronic transfusions. Alloimmunization prevalence in transfused patients with bone marrow failure syndrome (BMFS) is unknown. This study aimed to determine physician practice for RBC antigen matching, immunization rates, and antibody specificities in patients with BMFS. STUDY DESIGN AND METHODS The clinical records of all patients with BMFS seen at the Children's Hospital of Philadelphia between 2001 and 2015 were reviewed. Immunization rate was determined per 100 units transfused. RESULTS ABO/D, C, E, and K (CEK) RBC matching was requested for 21.8% of patients. A total of 3782 RBC units were transfused to 87 patients, of which 2551 (67.5%) were CEK matched and 1231 (32.5%) were ABO/D only matched. The majority of units transfused to patients on a chronic transfusion regimen were CEK matched (89.6% of 2728 units). No anti-C, -E, or -K antibodies formed in any patient during the 14-year study period. Two alloantibodies and two autoantibodies formed, resulting in a rate of 0.05 alloantibodies and 0.05 autoantibodies per 100 units transfused. The prevalence of alloimmunization was 2.3%. CONCLUSION The rate and prevalence of RBC alloimmunization were low in patients with BMFS. CEK matching avoided alloimmunization to these antigens in chronically transfused patients.

Diamond Blackfan anemia (DBA) is a rare, inherited bone marrow failure syndrome characterized by anemia, congenital anomalies and a predisposition to cancer. The patients usually present during infancy or early childhood, but can also present in adulthood. In the majority of cases DBA is due to a mutation in a small or large ribosomal protein (RP) subunit leading to RP haploinsufficiency. The only treatments for the anemia of DBA are red cell transfusions (accompanied by iron chelation), oral corticosteroid therapy or stem cell transplantation. Pospisilova et al. (Haematologica 2007; 92(5):e66-67) reported one complete and two partial erythroid responses after the use of the branched chain amino acid L-leucine in 6 select patients. In skeletal muscle, leucine supplementation can upregulate components of the protein synthetic machinery, including ribosomal proteins, promoting protein translation. Mouse and fish models of DBA respond with amelioration of anemia to L-leucine. We therefore proposed to study the effect of L-leucine on transfusion dependence and growth in subjects with DBA. Methods: The primary objectives were to determine the feasibility of administering L-leucine in subjects with DBA who are red cell transfusion-dependent and to determine the efficacy of L-leucine to produce a hematologic and growth response. The secondary objective was to determine the safety profile of L-leucine. Twelve study sites were involved in this multi-center, Phase I/II study with an anticipated accrual of 50 subjects. A dose of 700 mg/M2 orally three times per day for 9 months was used. Inclusion criteria included age > 2 years, the diagnosis of DBA and transfusion dependence with adequate kidney and liver function. Response was evaluated at 9 months with Complete Response (CR) defined as no further transfusions required and Hb >9; Partial Response (PR): Hb < 9 gm/dL with an increase in reticulocyte count and transfusion interval; and No Response (NR): no change in transfusion needs, Hb or reticulocyte count . Growth percentiles were evaluated at baseline and at completion of 9 months of treatment and the growth velocity change was calculated. Results: The study opened July 2014 and closed February 2017; 55 subjects were consented; 12 were screen failures; 43 subjects were evaluable. There were 21 males; the median age was 9 years 1 month (2 years 5 months - 46 years 1 month). There were no untoward side effects experienced by any subject that were attributable to the L-leucine. Two subjects had an erythroid CR and 1 subject had a PR. The CRs occurred at 1 month and 3 months after start of L-leucine. The subject with PR had an elevated reticulocyte count but was not able to maintain a Hb >9 gm/dL without a transfusion and thus was not transfusion independent. Of the 30 subjects with growth potential who received L-leucine 10 experienced a positive growth velocity change at 9 months of therapy compared to baseline. At a median age of 7.5 years, the mean pre-leucine height percentile was 27 +/- 17.9 and the post-leucine height percentile was 35 +/- 19.9 (p Conclusions: The administration of L-leucine is safe. L-leucine administration resulted in an erythroid response in 7% of subjects and an increased growth velocity in 33% of growing subjects. Based upon extrapolation from animal models, it is likely that this dose was suboptimal. We hypothesize that higher doses of L-leucine will lead to hematologic responses in more subjects who are transfusion dependent. The potential benefit of added growth in children with DBA may improve final adult height. Disclosures Glader: Agios: Consultancy, Research Funding.

[Figure][1] A 4-year-old girl with a known history of methylmalonic acidemia (MMA) complicated by acquired hypothyroidism, failure to thrive, and developmental delay developed pancytopenia during an admission for emesis and metabolic acidosis. She had no symptoms of a viral infection, and

[Figure][1] A 23-year-old man presented to our clinic for a second opinion. He was given the diagnosis of myelodysplastic syndrome (MDS) years prior, based on a history of iron overload and bone marrow biopsy findings of a hypercellular marrow with erythroid hyperplasia and

This article provides a practice-based and concise review of the etiology, diagnosis, and management of acquired aplastic anemia in children. Bone marrow transplantation, immunosuppressive therapy, and supportive care are discussed in detail. The aim is to provide the clinician with a better understanding of the disease and to offer guidelines for the management of children with this uncommon yet serious disorder.

Familial hemophagocytic lymphohistiocytosis is an inherited deficiency of natural killer cell function and excessive cytokine activity, which predominantly presents in early childhood. The initial symptoms of familial hemophagocytic lymphohistiocytosis are often nonspecific but may be predominantly neurologic. The case presented here describes an 18-month-old boy who initially presented with fever, encephalopathy, and hemiparesis. He had innumerable brain lesions visualized on magnetic resonance imaging scans. An infectious etiology was excluded, and brain, liver, and bone marrow biopsies were nonspecific but consistent with hemophagocytic lymphohistiocytosis. Cells were sent for flow cytometry perforin analysis, which demonstrated defective natural killer cell function. A diagnosis of familial hemophagocytic lymphohistiocytosis was confirmed by mutation analysis and decreased expression of the perforin gene, in the patient and immediate family members. These results showed the patient to be a compound heterozygote for perforin mutations. His case illustrates the potential for a fulminant neurological presentation of familial hemophagocytic lymphohistiocytosis with widespread lesions in the brain.

Abstract 262 Introduction: The most common cause of neurological injury in sickle cell anemia is silent cerebral infarcts (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial (SIT Trial) cohort, we sought to identify risk factors associated with SCI. Patients and Methods: In this cross-sectional study, we evaluated the clinical history, baseline laboratory values and performed magnetic resonance imaging of the brain. For those children with SCI-like lesions, a pediatric neurologist examined the child and neuroradiology and neurology committees adjudicated the presence of SCI. Children between the ages of 5 and 15 years with hemoglobin SS or S-beta° thalassemia and no history of overt strokes or seizure were evaluated. Results: A total of 542 children were evaluated; 173 (31.9%) had SCI. The mean age of the children was 9.3 years, with 280 males (51.7%). In a multivariate logistic analysis, two covariates were significant: a single systolic blood pressure (SBP) obtained during a baseline well-visit, p = 0.015 and hemoglobin F (Hgb F) level obtained after three years of age, p = 0.038. Higher values of SBP and lower values of Hgb F increased the odds of SCI; Figure. Baseline values of white blood cell count, hemoglobin level, oxygen saturation, reticulocytes, pain, or ACS event rates were not associated with SCI. Conclusion: SBP and Hgb F level are two previously unidentified risk factors for SCI in children with sickle cell disease. Modulation of SBP and Hgb F levels might decrease the risk of SCI. Disclosures: No relevant conflicts of interest to declare.