ALBERT

Description: Background: Sickle cell disease (SCD) is a complex genetic disorder affecting mainly people of African origin. A hallmark of SCD is vaso-occlusive crisis (VOC) - this event is acutely painful and the primary cause of hospitalization in SCD patients. VOC can lead to life-threatening complications such as acute chest syndrome. SCD is also associated with chronic complications including pulmonary hypertension, damage to organs and shortened life expectancy. Therefore, effective management and treatment strategies are essential to reduce burden of illness and ensure high quality of life for the patient. Aim: To survey the treatment and management strategies used by patients with SCD, and to determine patient satisfaction levels. Methods: SWAY is an ongoing multi-country, cross-sectional survey of SCD patients, caregivers and treating physicians. The survey, conducted online and in print, includes 6 categories: demographics, symptoms, impact of disease and use of a caregiver, impact on work and finances, disease management/treatment approaches, and patient-physician relationship. Where relevant, questions include a 7-point severity scale for each statement; a score of 5−7 indicates 'high severity/impact'. Patient enrollment is via treating physicians and patient association groups. The enrollment target is approximately 2000 patients. Results: To date, 1513 SCD patients (48% male, mean age 24.1 years, 63% HbSS and 30% HbSC disease) have been surveyed from 11 countries across North and South America, Europe and Africa. When considering the main person responsible for SCD treatment and management, patients primarily reported management by an SCD specialist (59% of patients) or GP/family doctor (20%). Most patients were satisfied with the frequency of interaction with their doctor (78%) and reported they are confident they are being assessed and treated properly (66%; based on high-impact scores 5−7). Accordingly, 60% of patients (scoring 5−7) reported sharing the same goals for SCD management and treatment as their doctor. The most common treatment goals for patients are to improve quality of life (80% of patients), prevent SCD worsening (59%), improve long-term survival (42%) and improve overall symptoms (40%). Patients reported receiving ongoing treatment with folic acid (58%), antibiotics (37%), anti-inflammatories (37%), over-the-counter pain medication (37%), opioids (35%), hydroxyurea (23%), blood transfusions (10%) and L-glutamine (4%). Having surgery or a medical procedure to manage their SCD was reported by 47% of patients, with gall bladder removal (16%), port placement (15%) and splenectomy (11%) being the most frequent. Although 63% of patients (scoring 5−7) indicated satisfaction with their treatment received to manage their SCD, 75% of patients (scoring 5−7) agreed they would like an alternative treatment to their current pain management medication, and 67% of patients would like additional professional emotional support. In the 12 months before survey completion, 7829 VOCs were reported (mean of 5.2 VOCs per patient); 8% of patients experienced 0 VOCs, 51% experienced 1−4 VOCs and 40% experienced ≥5 VOCs. Of these, 38% of VOCs led to overnight hospitalization, 24% were managed at home and 19% were treated in the emergency room. The main reasons that patients chose to manage their VOCs at home include a previous poor experience at hospital (40%), the opinion that medical assistance was not required (28%), the perception that medical professionals do not understand SCD (27%) and the cost of hospital treatment (22%; 41% of patients have no health insurance). Patients who self-managed their VOCs primarily did so with rest/sleep (73%), by drinking fluids (72%) and with opioid-based analgesia (58%). Conclusions: This interim analysis of the SWAY survey suggests that although many patients report satisfaction with their current level of management and treatment, there is still a need for additional healthcare support and alternative treatments. Underlining this, many patients experiencing VOCs do not seek medical assistance despite the potential for life-threatening complications, and 〉75% of patients surveyed are not receiving hydroxyurea even though the majority are cared for by SCD specialists. Further data collection and analysis will highlight any geographic differences in SCD management strategies and help identify any region-specific unmet patient needs. Disclosures James: Novartis: Honoraria; Sickle Cell Society: Employment. Andemariam:NovoNordisk: Membership on an entity's Board of Directors or advisory committees; New Health Sciences: Membership on an entity's Board of Directors or advisory committees; Emmaus: Membership on an entity's Board of Directors or advisory committees; Cyclerion: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Imara: Research Funding; Global Blood Therapeutics: Other: DSMB Member; Community Health Network of Connecticut: Consultancy; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Terumo BCT: Membership on an entity's Board of Directors or advisory committees. El-Rassi:Novartis Pharmaceuticals: Research Funding. Francis-Gibson:Sickle Cell Disease Association of America: Employment. Nero:Novartis: Consultancy. Minniti:Doris Duke Foundation: Research Funding. Trimnell:Novartis: Consultancy; Global Blood Therapeutics: Consultancy; Cyclerion: Consultancy. Abboud:Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Modus: Research Funding; CRSPR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Other: Travel support; Eli Lilly: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; GBT: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Colombatti:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Addmedica: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees. de Montalembert:AddMedica: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jastaniah:Novartis: Consultancy, Honoraria. Nur:Novartis: Consultancy. DeBonnett:Novartis Pharmaceuticals Corporation: Employment. Osunkwo:Micella Biopharma: Other: DSMB Member ; Terumo: Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau.

Description: Background: Renal disease is a common end organ complication of sickle cell disease(SCD). Risk factors of sickle cell nephropathy include age, genotype, and anemia. We have investigated and discovered Lower Hemoglobin Oxygen Saturation levels associated with microalbuminuria. To further investigate this, we investigated a patient's history of asthma as a risk factor of renal disease. Asthma has been linked to increased mortality in adult and children with SCD from the National Cooperative SCD Study Group. In our ongoing International CASIRE Renal Cohort study, we investigated the clinical history of asthma and laboratory correlates of albuminuria and proteinuria as measured by Urine Protein/Creatinine and Urine Albumin/Creatinine . Methods: 538pediatric and adult SCD (3-59 y/o) patients were recruited at baseline from 6 Centers (USA: Univ of Michigan, Case Medical Center/Rainbow Babies, Albert Einstein-Montefiore Medical Center, Univ of Connecticut; Italy: Univ. of Padova, Univ of Naples;). Clinical history and laboratory studies, including Pain crisis patterns, SBP, DBP, BMI, CBC, Serum Crt, Urine ph, Urine SG were collected. For this report, we concentrated on patient's comorbidities and sickle cell medical history, specifically pain crisis patterns, acute chest history and asthma. Urine Microalbumin/Crt(UMA) (mg/gm) was obtained in 172 patients and we categorized patients into No Albuminuria: (No UMA)300mg/gm.334 subjects answered the question of medical history of asthma and of those 172 had Urine Microalbumin (UMA) levels. 75% of SCD-Asthma group (N=56) and 78% of SCD-NoAsthma group (N=204) had severe SCD (SS or SBeta Zero). Children (

Description: Introduction: Millions are affected by Sickle Cell Disease (SCD) worldwide with the greatest burden in sub-saharan Africa. Its origin thought to lie within the malaria belt of the world, SCD continues to affect thousands of lives worldwide partly due to the migration patterns of the human race to different continents. We created the Consortium for the Advancement of Sickle Cell Research (CASiRe) to better understand the different phenotypes of SCD and compare the clinical profiles of patients living in different environments through a validated questionnaire and medical chart review, standardized across 4 countries (United States[U.S.] United Kingdom[U.K.], Italy and Ghana). For this report, we recorded the multi-generational ethnic and racial background of 877 SCD patients across the CASIRE cohort for our final analysis. Methods: CASiRe included 6 sites in the U.S. (Univ. of Michigan, Rainbow Babies & Children's Hospital, Promedica Toledo Children's Hospital, Children's Hospital at Montefiore, Connecticut Children's Medical Center, Univ.of Connecticut Health Center), 2 in Ghana(Ghana Institute of Clinical Genetics, Pediatric SCD Clinic at Korle Bu Teaching Hospital), 2 in Italy( Univ. of Campania Luigi Vanvitelli, Univ. of Padua, Italy), and U.K.(Guys & St. Thomas Hospital, Evelina Children's Hosp). Between 2011 and 2017, after obtaining IRB approval at each site and written informed consent, demographic, clinical and laboratory data were collected by interviewing the patient and/or parent/guardian At the 2 sites (Guys and St Thomas Hospital, UK; Univ. of Padua, Italy) with existing IRB approved SCD registries data were abstracted directly from their respective databases. Descriptive statistics were performed on a subset of demographic data that included: age, race, gender, sickle cell genotype, country of birth of patient, parents, and grandparents. The geographic region and country of origin was based on parents' country of birth and separated into 10 regions: W.Africa, C.Africa, N Africa, Caribbean, C. America, N America, Europe, S America, Asia, Middle East. Results: 877 patients were enrolled with a median age 19.3 years. 451 (51.4%) patients were children, 424 (48.3%) male. Ghanaians represented 41.6% (365) of patients, while 254 patients (29%) were from the U.S. Italy enrolled 81 patients (9.2%), and 177 patients (20.2%) were from the U.K. West Africa represented the largest geographic region of origin of(577/65.8%), followed by N. America (184/21%), Caribbean (51/5.8%), Europe (27/3.1%), and Central Africa (24/2.7%). Overall(Fig. 1), 75% of patients (658) had Hgb SS, 168 patients (19.2%) had Sickle C disease, 29 (3.3%) had Sβ+thal and 22 patients (2.5%) of patients had Sβ0 thal. Racially, 820 patients (93.5%) identified themselves as African American or Black, while 30 patients (3.4%) identified themselves as Caucasian and 21 patients (2.4%) identified themselves as Latino or Hispanic. All Ghanaians identified as Black, while in the US and UK, over 90% of patients identified themselves as Black, and about 3% reported themselves as Caucasian. In comparison, in Italy, over 76% of patients reported a Black racial background, while 21% reported Caucasian background. (Table 1 and 2)〉98%Ghanaian patients and their parents were born in Ghana. In contrast, 66.7% of patients and 90% of patients were born within the US; Parents of patients were born in America 70% of the time. Caribbean (12.5%) and West African countries(9.5%) were the next highest parent countries of origin. 32 different countries of origin were reported within our cohort with the US leading with 22 different countries. Conclusion: This study is the first to describe the geographic distribution of these migrations in a very large cohort of nearly 900 patients with SCD.West Africa represented the largest geographic region of origin for SCD patients in Europe while Caribbean was the leading Non-US geographic region of origin in American patients. The diverse ethnic backgrounds observed in our cohort raises the possibility of how genetic and environmental heterogeneity within each SCD population subgroup can have implications on the clinical phenotype and clinical research outcomes. Disclosures Campbell: Novartis: Research Funding; Cyclerion: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding. Colombatti:Novartis: Consultancy; Global Blood Therapeutics: Consultancy; AddMedica: Consultancy. Andemariam:NovoNordisk: Membership on an entity's Board of Directors or advisory committees; New Health Sciences: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Other: DSMB Member; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Emmaus: Membership on an entity's Board of Directors or advisory committees; Cyclerion: Membership on an entity's Board of Directors or advisory committees; Imara: Research Funding; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Community Health Network of Connecticut: Consultancy; Terumo BCT: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Strunk:Novartis: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Speakers Bureau. Piccone:Hemex Health, Inc.: Patents & Royalties. Manwani:GBT: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Consultancy. Perrotta:Novartis: Honoraria, Research Funding; Acceleron Pharma: Research Funding.

Description: Introduction Sickle cell anemia is the most common single gene defect in the United States, affecting approximately 100,000 individuals (Hassel Am J Prev Med 2010). It is characterized by chronic hemolysis, unpredictable vaso-occlusive episodes (VOEs), and chronic organ damage leading to early death in patients affected by the disorder. Hydroxyurea, a small molecule chemotherapeutic agent, has been used to treat patients with severe sickle cell disease since 1984 (Brawley Ann Intern Med 2008). Two randomized controlled trials, the Multicenter Study of Hydroxyurea (Charache N Engl J Med 1995) in adults and the Baby HUG trial (Wang Lancet 2011) in children, showed that hydroxyurea reduced the number of VOEs and hospital admissions, while simultaneously increasing hemoglobin and fetal hemoglobin in patients with sickle cell anemia. The goal of this study was to determine the clinical effectiveness of hydroxyurea in reducing the number VOEs and hospitalizations in unselected patients with sickle cell anemia. Methods The CASIRE group is an international multi-institutional collaborative group evaluating the clinical severity of patients with sickle cell anemia through a validated questionnaire, chart review and laboratory studies. Patients were enrolled on the CASIRE study after informed consent and assent was obtained from either the parent or patient when appropriate. The study was approved at each participating institution's IRB. A questionnaire was answered by the parents and/or patient, and baseline and current laboratory studies were collected. Patients were stratified into those who were not on hydroxyurea, and those who were currently on hydroxyurea. Number of VOEs, admissions, baseline and current fetal hemoglobin, and change in hemoglobin and MCV were compared. Results There were 349 patients in this study (134 on hydroxyurea). Baseline laboratory data are reported in table 1. Hemoglobin level and MCV were not statistically different in patients prior to and after taking hydroxyurea (table 2). Fetal hemoglobin in adults increased 2.7 times baseline, whereas in children it was unchanged. All patients on hydroxyurea had a reduction of VOEs, ED visits and admissions compared to prior to hydroxyurea (see table 3). Table 1. Baseline laboratory data Baseline data Patients on Hydroxyurea Patients not on Hydroxyurea Pediatric Adult Pediatric Adult N 78 56 140 75 Age 10 26.9 8.6 28.3 Hemoglobin (g/dL) 8.7 9.7 9.39 9.4 MCV (fL) 91 91.5 79 86 Fetal Hemoglobin (%) 15.1 12.4 9.6 5 Table 2. Clinical data for patients on HU Patients on Hydroxyurea Pediatric (78) Adult (56) Dose of HU (mg/kg) 23.8 20.5 # doses missed/wk 1 1.55 Fetal Hemoglobin on HU (%) 14.5 13.8 D MCV from baseline (fL) +5.4 +0.1 D Hgb from baseline (g/dL) +0.23 +0.4 Table 3. Number of pain episodes in patients on HU. Prior to HU In last year on HU 2 tailed paired t test Pediatric patients (N = 78) # pain episodes/year 25 12.9 0.62 # requiring ED/year 2.66 1 0.93 # requiring admission/year 4.28 1.79 0.017 Adult patients (N = 56) # pain episodes/year 36.7 28.6 0.021 # requiring ED/year 5.7 2.4 0 # requiring admission/year 6.6 3.15 0.117 Conclusion The Multicenter Study of Hydroxyurea and the BABY HUG study showed that hydroxyurea is efficacious for patients with sickle cell anemia. No previous study has evaluated the effectiveness of hydroxyurea in clinical practice. Our study suggests that, although baseline and current laboratory values are similar in patients prior to versus after taking hydroxyurea, there was a clear reduction in the number of VOEs and admissions, similar to the Baby HUG and MSH studies. These results suggest that the reduction of VOEs could be the product of a generalized decrease in overall inflammation and hemolysis or increased nitric oxide production rather than an increase in fetal hemoglobin by itself. Reasons for the similarity in laboratory values could include the length of time patients have been on hydroxyurea or that hydroxyurea was not escalated to maximum tolerated dose. Another reason may be the degree of compliance of patients in a clinical setting. We noted that 1/3 of our pediatric and ½ of our adult patients missed at least 1 dose of hydroxyurea per week suggesting that even partial compliance with hydroxyurea may prove beneficial clinically. This study demonstrates that hydroxyurea is effective in reducing the number of VOEs and admissions for unselected patients with sickle cell anemia. Disclosures No relevant conflicts of interest to declare.

Description: Background: Recent studies on the impact of migration on the geographical distribution of the HbS allele have highlighted sickle cell disease (SCD) as a global public health issue. Although considered a "rare disease" due to its global frequency in the 28 countries of the European Union, SCD is the most common genetic disease in France and the United Kingdom and its frequency is steadily rising in many other countries of central and southern Europe. At present, less than 50% of children with SCD have access to TCD screening in the USA and Europe. Most centers use the non-imaging approach, as described in the STOP trials, which is a "blind technique" where there is no guiding anatomical information and thus relies heavily on operator experience. Some centers now use imaging TCD which provides anatomical information enabling the Circle of Willis to be visualized and so facilitates identification of the basal cerebral arteries and orientation of the Doppler beam when acquiring blood velocities. The primary study objective was to determine the effectiveness of the modular training program in achieving the high level of scanning competency described in the STOP trial, irrespective of practitioner background and when using either non-imaging or imaging TCD. Methodology. The modular TCD training program was developed at the training center in London and delivered to trainees at all three centers (London-UK, Padova-Italy and Dublin, Ireland). The program comprised of a 2-day instructional course covering theory and practical aspects of TCD and incorporated significant hands-on instruction. This was followed by trainees scanning at their own hospital until they had collected a log book of at least 40 scans (within a one year period), after which a scan review and competency evaluation was performed. Results.Modular training program.Nine training courses were held (six in England, one in Ireland and two in Italy); these were attended by a total of 51 trainees (Table 1). Approximately half the trainees (45%) successfully completed the competency evaluation, 20 were still in training, two of whom had failed the assessment and eight withdrew from the program due to problems with local funding for staff or equipment. The ten trainees with an ultrasound background (clinical scientists) were able to acquire TCD skills rapidly as demonstrated by the high pass rate. The findings were more variable in the clinician group (pediatricians and nurses) with five requiring refresher courses and twelve failing to complete the minimum annual scan number (forty) due to small local sickle populations. Comparative analysis of TCD data obtained before and after training.A total of 555 patients were included in this study; 181 patients at Center 1 (52 males, mean age 7.9±3.8 (range 2-15.4 years), genotypes: 134 HbSS, 39 HbSC, 8 HbSβ thalassemia), 194 patients. Center 2 (53 males, mean age 7.4±3·2 (range 2-15.1 years), genotypes: 158 HbSS, 32 HbSC, 4 HbSβ) and 154 patients at Center 3 (50 males, mean age 6.4±3.5 (range 2-15.1 years), genotypes: 154 HbSS, 10HbSC, 16 HbSβ thalassemia). There was no significant difference in gender distribution (Chi-Square=0.313, p=0.85), but more young patients were recruited in Center 3 (ANOVA, F=8.9, p

Description: Abstract 3247 Activation of the coagulation system is present in adults with Sickle Cell Disease (SCD) who display higher levels of thrombin-antithrombin complex (TAT), prothrombin fragment F1+2, D-dimer, tissue factor and platelet activity. Whether the activation of the coagulation system is a bystander phenomenon or a main determinant of clinical complications is under investigation. Although thrombotic complications in SCD arise since infancy, the coagulation system in children has been poorly explored. We performed a comprehensive and systematic evaluation of the coagulation system in children with SCD and investigated its possible role in the development of the main clinical manifestations of SCD in childhood. The following markers of hemostatic and endothelial function were evaluated during steady state: factor VIII activity (FVIII), von Willebrand factor antigen (vWF:Ag) and collagen binding activity (vWF:CBA), PAI-1 antigen (PAI-1:Ag), t-PA antigen (t-PA:Ag), D-dimer, P-selectin, Nitric Oxide (NO), F1+2, TAT, ADAMTS-13 antigen (ADAMTS-13:Ag) and activity (ADAMTS-13:act). Markers of hemolysis (hemoglobin, reticulocytes, aptoglobin, bilirubin, LDH), inflammation (white blood cells, neutrophils, C reactive protein) were measured. Children were not in chronic transfusion. Magnetic Resonance (MRI), Angio Magnetic Resonance (MRA), Transcranial Doppler (TCD), Tricuspid Regurgitant Velocity (TRV) data and frequency of clinical complications were correlated with coagulation parameters. Continuous variables were compared using two-sided Student's t-test and Mann-Whitney non-parametric test, categorical variables using Chi-square and Fisher's exact test. Correlations between variables were evaluated by the Pearson or Spearman coefficient. Thirty-five HbS/HbS- 3 HbS/betathalassemia° (20 M and 18 F, mean age 6.49 years), and 6 HbS/HbC patients (3 M and 3 F, mean age 11.2 years) were evaluated. 60% of HbS/HbS and HbS/betathalassemia° children presented higher level of FVIII, D-dimer, F1+2 and lower level of NO, revealing coagulation activation since early age in HbS/HbS and HbS/betathalassemia° but not in HbS/HbC (Table 1). Coagulation variables correlated positively with markers of inflammation, hemolysis, endothelial activation demonstrating a broad involvement of the coagulation system in these processes, while correlated negatively with HbF (Table 2). No correlation was seen between coagulation variables and cerebral large vessel vasculopathy investigated by TCD and MRA nor TRV (p 〉0.05). Patients with Silent Infarcts on MRI (n.9) showed significant decrease in t-PA (4.53 vs 7.67, p 0.03) and ADAMTS-13 Ag (1.15 vs 1.50, p 0.05) -suggesting the presence of endothelial dysfunction- and a tendency toward higher D-dimer (2879.01 vs 1569.51), F1+2 (319 vs 231), TAT (17.17 vs 10.46) -suggesting a trend towards enhanced clotting activation compared to patients without Silent infarcts (n.21). Increase in D-dimer was associated with a Relative risk of 6 (p

Description: The diagnosis of patients with inherited anemias is increasingly made in conjunction with high-throughput 'next-generation' sequencing (NGS) analysis, largely using targeted resequencing panels validated for clinical use in diagnostic labs. While there is a joint UK NEQAS and European Molecular Quality Network pilot scheme for Molecular Genetics to assess NGS quality control, this is not disease-specific. Patients with inherited anaemias can have multiple mutations with complex genotype phenotype interactions therefore a scheme assessing interpretation of these results could be of value. Likewise, guidelines for variant reporting (eg ACMG- American College of Medical Genetics and Genomics) provide excellent advice on how to interpret the likely pathogenicity of genetic variants, but no disease-specific guidance exists to assist in the clinical interpretation of NGS findings for individuals with rare inherited anemias. The European Hematology Association Scientific Working Group on Red Cells and Iron carried out a survey among its members to investigate variability in current practice and determine the need for, and feasibility of, a formal external quality assessment (EQA) scheme. Surveys and two clinical vignettes with sample variant call files (VCFs) were distributed among 14 participating labs from 9 countries; 13/14 labs used a targeted panel and 1/14 lab (8%) used a 366-gene virtual panel derived from whole exome sequencing data. Accreditation: 12/14 labs had ISO (International Organisation for Standardisation) accreditation for their NGS; 2/12,used local accreditation schemes. The number of genes per targeted panel ranged from 18 to 215 genes (median 64), covering: congenital dyserythropoietic anemias, Diamond-Blackfan anemia, sideroblastic anemia, red cell membrane and enzyme disorders. Some panels included other related bone marrow failure or iron metabolism disorders. 7/13 labs with targeted panels sequenced only exons, with variable padding into introns, while 6/13 routinely sequenced 3' and 5' untranslated regions. Capture methods were variable between labs and 11/14 labs used Illumina platforms for sequencing and 3/14 Ion Torrent. Sanger sequencing was used for confirmation of NGS variants in 12/14 labs, but used for gap-filling of uncovered regions in 10/14 labs. Reporting of variants followed ACMG guidelines in 10/14 labs, ACGS (Association for Clinical Genomics Science) guidelines in 2/14 and no published guidelines in 2/14. Reporting of Tier 3 (variants of uncertain significance): 8/14 labs reported strict adherence to ACMG guidelines, including only Class 4 and Class 5 variants in clinical reports, while 6/14 labs admitted looser adherence and reporting of Class 3 variants depending on circumstances. The number of samples analysed per year was highly variable between labs (10-600, median 60). Two mini-EQA VCFs were sent with clinical vignettes, for which 100% of labs correctly identified a case of autosomal recessive sideroblastic anaemia due to compound heterozygous mutations in SLC25A38, and 100% correctly identified a case negative by NGS. Class 3 variants were not reported at all in 50% of clinical reports, reported in the main body of the report in 20% and in a separate table in 30% of labs. In conclusion, we have identified common approaches to NGS sequencing in 14 diagnostic laboratories but highlighted variability in accreditation, use of Sanger sequencing and adherence to ACMG guidelines. The feasibility of carrying out an EQA scheme has been established and work will continue with UK NEQAS to formally create such a scheme, with the aim of ensuring improved patient care through the use of objective quality assessments. Disclosures Colombatti: ADDMEDICA: Consultancy; BlueBirdBio: Consultancy; Global Blood Therapeutics: Consultancy; NOVARTIS: Consultancy. Viprakasit:Protagonist Therapeutics: Consultancy, Research Funding; Agios: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Description: Background Routine use of Transcranial Doppler (TCD) screening is standard management for the prevention of Stroke in children with Sickle Cell Disease (SCD). However, due to a number of factors including the lack of adequately trained TCD operators, less than 50% of children with SCD are enrolled in TCD screening programmes in the USA and Europe. This prospective, multi-centre study focused on the provision of TCD skills delivered through an educational programme. The study objectives were to determine the effectiveness of modular TCD training, to improve the quality and standardisation of TCD assessment and thereby facilitate an increase in the number of children screened. Methods The modular training programme comprised of a two-day course, covering theory and practical aspects of TCD and incorporating significant hands-on instruction. This was followed by local scanning with continuous monitoring and feedback from the training centre in the United Kingdom (UK). Competency evaluations were undertaken at the end of the instructional course and 6-12 months later when a log book of at least 50 scans was completed. TCD results were collected prospectively from a consecutive series of children by certified operators at each centre. Data were compared with that acquired from the same patients in the year prior to the training programme using imaging and/or non-imaging TCD. Statistical analysis was performed using Pearson Chi-Square controlling for possible treatment bias. Results Data were obtained from 326 patients (male 168 (51.5%); female 158 (48.5%); mean age 7.6±3.5, range 1-17) in the UK, Ireland and Italy. Genotypes were; HbSS 79%, HbSC 19%, HbSbetathalassemia° 1%, HbSbetathalassemia+ 1%. 462 pre-training scans (imaging and/or non-imaging TCD); 134 from the UK, 193 from Ireland and 135 from Italy, and 377 post-training scans were available; 114 from the UK, 167 from Ireland and 43 from Italy (Table). Statistical analysis revealed a significant difference in the STOP distribution between the three centres (C2=53, p

Description: Background: Determining Effects of Platelet Inhibition on Vaso-Occlusive Events (DOVE) was a multi-national Phase 3 trial to assess the efficacy of prasugrel for the prevention of vaso-occlusive crisis (VOC) as a composite endpoint of painful crisis or acute chest syndrome in children and adolescents aged 2-18 years with sickle cell anemia (SCA). Despite a trend toward fewer VOCs in the prasugrel-treated oldest age group (12-18 years), DOVE did not meet its primary endpoint. This was the first multinational prospective study of diary-reported pain rate and intensity in children and adolescents with SCA. Aim of current study: This sub-study evaluated VOC events (as defined by DOVE), analgesic use, and the rate, intensity, and perception of pain by geographical region and age group. Data: During the DOVE study, participants who were 4 years or older used daily diaries to report pain rate and intensity, and analgesic use. Rates of pain and analgesic use were calculated for each patient by summing the number of days with any pain or analgesic use reported divided by the number of non-missing diary entries from randomization to 9 months. Mean pain intensity was calculated similarly, but days in which participants reported pain of "0" were not included. Pain rate and intensity were evaluated only for participants 7 years or older. Type of analgesic use (opioid vs non-opioid) was also evaluated in all participants. Treatment arms (prasugrel-treated and untreated patients) were combined for the current analysis, as justified by the lack of a statistically significant treatment effect. Data were analyzed by univariable and multivariable methods. Results: There was no association between baseline hematology labs or lactic dehydrogenase levels and pain rate or intensity. In multivariable analysis, older participants (aged ≥12 years) reported more frequent pain than younger participants (p=0.0320). Hydroxyurea (HU) use at baseline did not affect pain rate or pain intensity. The regions of the Americas and West Europe showed higher pain rate and intensity scores than Africa and the Middle East. (Table 1) Opioid use was much higher in the Americas compared with other regions p=0.0002. (Table 2) Conclusions: Pain rates were higher in older children, demonstrating a worsening of pain during the lifespan, which is consistent with previous literature. Pain rate and intensity were similar irrespective of HU treatment; whether this finding reflects increased baseline pain in participants on HU or other causality is unclear. Regional differences in pain rate and intensity were seen. Pain intensity and opioid use were significantly higher in the Americas than in other regions. In contrast, the lowest reported pain rates and intensities were found in Africa. These findings suggest cultural and/or regional differences in SCA pain perception and reporting that require further exploration. The relationship between pain intensity and analgesic treatment practices also needs further study. Disclosures Kanter: Novartis: Consultancy. Heath:Eli Lilly and Company: Employment. Zhou:Eli Lilly and Company: Employment, Other: Minor Shareholder. Colombatti:Eli Lilly and Company: Research Funding. Dampier:Eli Lilly and Company: Consultancy, Research Funding. Hassab:Eli Lilly and Company: Research Funding. Brown:Eli Lilly and Company: Employment, Other: Minor Shareholder. Jakubowski:Eli Lilly and Company: Employment, Equity Ownership. Yao:Eli Lilly and Company: Employment. Knorr:Eli Lilly and Company: Employment, Equity Ownership. Hoppe:Eli Lilly and Company: Consultancy.

Description: Background: Acute Chest Syndrome (ACS) is the second cause of hospitalization in Sickle Cell Disease (SCD), burdened by significant morbidity and mortality. The guidelines regarding management of ACS are sometimes difficult to follow in the real world and the prevention and treatment strategies of ACS are often applied in an uneven manner in the various settings (community care, regional hospitals, reference university centers). Moreover, epidemiology, clinical phenotype and outcomes as well as risk factors could vary in different populations according to ethnicity, genotype or health care system organization. Aims and Methods: A retrospective multicenter observational study was conducted to investigate the epidemiology of ACS and to the evaluate the diagnostic and therapeutic pathways of ACS in children with SCD (age 0-18 years) in the 2013-2018 period, after the publication of the Italian Association of Pediatric Hematology Oncology (AIEOP) Guidelines for the Management of SCD in Childhood in Italy in 2012. Results: 126 children were recruited and 122 included in the analysis, with 208 evaluable episodes of ACS (range: 1-6 episodes /patient) from 11 AIEOP Centers. 73 M, 49 F. Mean age was 10.9 years. 85% patients were of African origin, 92% were HbSS/SB°; mean age at diagnosis of SCD of the entire cohort was 25,3 months (range 0-16,8). 44.2% of patients had more than one episode of ACS during the study period; 37% had had a previous episode before 2013. 58% had comorbidities, mostly respiratory (asthma or allergy). 75% of the patients underwent disease modifying treatment during study period (73% hydroxyurea, 2% chronic transfusion). The seasonality of ACS episodes was important in our country: 75% of episodes occured between October and March. 95% of ACS episodes were secondary to a Vaso-Occlusive Crisis. 76% of the admissions occurred in SCD reference centers, 24% in regional hospitals, but 30% later required transfer to reference centers for worsening of clinical conditions or need of exchange transfusion. The mean length of hospitalization was 9.6 days (range 1-46); one patient died of pneumococcal sepsis; 6 episodes required transfer to the Intensive Care Unit, mechanical ventilation was required in one episode. A good adherence to the AIEOP Guidelines was documented for some aspects: 99% of the patients were hospitalized, 98% performed chest X-ray for the diagnosis of ACS and in 99% antibiotic therapy was started. Others aspects were less satisfactory and in need of improvement: incentive spirometry was only performed in 19% of admissions; oxygen therapy was performed only in 75% of patients even if SatO2 was8g/dl, while in 16% an exchange transfusion was performed for severe respiratory distress (of these 71% were performed in patients transfered from regional hospitals); 38% required inhaled bronchodilators, 6% steroids. A preliminay evaluation of risk factors for recurrent ACS showed that in our cohort allergy to inhaled allergens (p 0.02) and enuresis (p 0.01) were associated with increased prevalence of recurrent ACS; patients with asthma/wheezing also presented more recurrent ACS compared to patients wihout them (23% vs 13%) but this data did not reach statistical significance. Conclusion: This study represents the first analysis in Italy of ACS, which is confirmed as a frequent event in our cohort, with a significant proportion of patients who experience recurrent ACS. Steps need to be undertaken to improve management of ACS and adherence to the AIEOP guidelines at a national level: stimulate the application of early preventive measures that are still under-utilized, increase the appropriateness of multidisciplinary specialist approach (transfusion specialist, acute care physicians, pneumologists, hematologists) strengthen the dissemination of information through training events for all the Hospitals of the network. Disclosures Colombatti: AddMedica: Consultancy; Global Blood Therapeutics: Consultancy; Novartis: Consultancy.