Outcomes of Patients with Sickle Cell Disease and Eskd in the Usrds Registry

Abstract Introduction: Patients with sickle cell disease (SCD) and kidney disease are at increased risk for mortality; understanding the outcomes of end stage kidney disease (ESKD) highlights the importance of monitoring the progression of kidney disease, target interventions, and highlight disparities in care. We obtained data from the United States Renal Data System (USRDS) from 1998-2017 to understand potential risk factors for developing ESKD, outcomes, and access to organ transplantation. Methods: We abstracted predictor variables including age, sex, race, ethnicity, first ESKD treatment type, comorbid conditions, and hydroxyurea use at the time of ESKD from the Centers for Medicare and Medicaid Services (CMS). We recorded outcome variables including 1-year mortality after ESKD treatment initiation, transplant within 1 year after ESKD treatment initiation, and 1-year graft rejection rate. All values were adjusted for age (on a continuous scale), sex, ethnicity, initial treatment modality, hemodialysis access type, pre-ESKD nephrology care, and comorbidities. One-year mortality, transplant rate, and graft rejection rate were estimated for all patients. Unadjusted and adjusted odds ratios, with 95% confidence intervals, were calculated using logistic regression. All statistical analysis was performed in SPSS (Version 27.0; IBM Corp, Armonk, NY). A P value of <.05 was considered significant. Results: We identified 1920 black SCD patients and 598,726 black non-SCD patients that developed ESKD from 1998-2017. SCD patients developed ESKD earlier than non SCD patients (adjusted OR: 0.62 (0.61 ,0.64). The mean age of ESKD diagnosis was 43.3± 13.3years for black SCD patients as compared to 58.4±15.5 years for non-SCD black patients. Importantly, 20% of black SCD patients developed ESKD prior to age 30 as compared to 8.5% of non-SCD patients. Male patients with SCD developed ESKD earlier than female patients (median 42 vs 46 years, p<0.001). At the time of ESKD, 12% of SCD patients were receiving hydroxyurea. After adjusting for age, sex, ethnicity, first ESKD treatment, SCD patients with ESKD had higher odds of having congestive heart failure and cerebrovascular disease. SCD patients with ESKD had a higher one-year mortality rate than non-SCD patients (adjusted OR: 2.24 95%CI:2.03-2.47). The overall one-year mortality was 26.2% in black SCD patients with ESKD and 17.4% in black non-SCD ESKD. The one-year mortality in black SCD patients with ESKD decreased from 28.4% (1998-2005), 27.0% (2006-2010) to 22.8% (2011-2017). Patients with SCD were less likely to receive a kidney transplant than those patients without SCD (OR: 0.63, 95% CI:0.45-0.87). We identified no difference in graft rejection between SCD and non-SCD ESKD patients. (OR: 1.11, 0.6-2.04) Conclusion: The USRDS database continues to demonstrate that patients with SCD develop ESKD earlier in life than race matched controls and have a higher one-year mortality after being diagnosed with ESKD. Additional research is needed to understand why male patients are at higher risk of developing ESKD earlier than females and whether genetic or clinical modifiers impact the high prevalence of ESKD in patients <30 years. Additional public health measures are needed to decrease the disparities in access to organ transplantation. As hydroxyurea may be discontinued due to ESKD-associated anemia, prospective studies should be conducted to determine the role of SCD modifying therapies or other renoprotective agents in delaying progression to ESKD. Figure 1 Figure 1. Disclosures Ataga: Novartis: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy; Forma Therapeutics: 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; F. Hoffmann-La Roche Ltd: Consultancy; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Lebensburger: Novartis: Consultancy; Bio Products Laboratory: Consultancy.

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Comprehensive Structured Transition Program with Dedicated Transition Navigator Reduced Lost to Follow-up and Improved Medication Adherence in Sickle Cell Disease and Thalassemia Adolescents and Young Adults

Blood ◽

10.1182/blood.v128.22.317.317 ◽

2016 ◽

Vol 128 (22) ◽

pp. 317-317

Author(s):

Brooke Allemang ◽

Kate Allan ◽

Colleen Johnson ◽

Melina Cheong ◽

Patrina Cheung ◽

...

Keyword(s):

Medication Adherence ◽

Sickle Cell Disease ◽

Board Of Directors ◽

Transition Program ◽

Cell Disease ◽

Advisory Committees ◽

Appointment Attendance ◽

One Year ◽

Lost To Follow Up

Abstract Introduction: Adolescents and young adults (AYA) with sickle cell disease (SCD) and thalassemia transitioning from pediatric to adult health care experience a lack of engagement with adult care providers, are at high risk of loss to follow-up, emergence of psychosocial issues, morbidity and mortality. The shift from a pediatric to an adult setting can be challenging for AYA who are coping with multiple life transitions and are expected to acquire the necessary skills to manage their own care. Hypothesis: implementation of a comprehensive structured transition program with dedicated transition navigator (TN) in a pediatric and adult hemoglobinopathy comprehensive care center will reduce loss to follow-up and hospitalization, improve adherence to medication and attendance to appointments compared to an unstructured transfer from pediatric to adult program. Methods: A structured comprehensive transition program with a dedicated TN, based on a quality improvement framework with an iterative design to refine the intervention over time, was developed and deployed across a pediatric and adult hemoglobinopathy comprehensive care center (Hospital for Sick Children (HSC) and Toronto General Hospital (TGH) respectively) starting August 1, 2014. Prior to this, patients at age 18 were transferred without preparation. With the TN model, adolescents, from age 12 were followed at each visit by the TN and up to one year after transitioning. Prior to transition to the adult center, adolescents were seen jointly by pediatric and adult care providers and TN in a transition clinic. Patients were assessed for transition readiness and provided with tailored education at each appointment. This observational study compared all AYA with SCD or thalassemia who turned 18 years between August 1, 2013 and August 1, 2015. Patients in the cohort prior to the comprehensive transition program were compared to patients who transitioned through the formal program. Data from one year prior to last appointment at HSC and one year after the first appointment at TGH were collected. The effects of covariates on imaging/clinic/transfusion/subspecialist appointment attendance, medication adherence and hospitalizations were analyzed by multivariable regression. Results: 112 patients met the criteria for transfer/transition, of which 51 transferred prior to August 1, 2014 and 61 transitioned through the comprehensive transition program. No significant differences were observed in baseline demographics including age at transfer/transition, phenotype, distance from the center, medications, parental/guardian appointment attendance, immigration status, family structure, first language spoken or documented cognitive impairment. The youngest patient to undergo transition in the observation period was 16.6 years. The transition process significantly reduced the proportion of patients lost to follow-up from 29% (11/38) to 7% (4/57) (P = 0.0335, Figure 1). In patients who were on hydroxyurea or iron chelation, significant increase in the proportion of patients who maintained or improved their medication adherence to 4 or more days a week was observed in the transition cohort (P = 0.047, LR 4.668) and the presence of the transition program was independently associated with the improvement. A trend towards improvement or maintenance of ≥ 90% attendance to appointments was observed (P = 0.096, OR 2.254). Variations in appointment attendance can be explained by patient's age, distance from the comprehensive hemoglobinopathy center, and English as patient's first language. No independent predictor was found in frequency of hospitalization. No new overt strokes or deaths occurred in the year after moving to the adult center. Conclusions: Comprehensive structured transition program with dedicated transition navigator significantly reduced the number of AYA lost to follow-up, and significantly improved and maintained fair to good medication adherence. Further analysis of economic benefit and patient satisfaction will be conducted. A clustered randomized-controlled trial will be forthcoming to determine the effectiveness of this transition model of care on AYA patients with sickle cell disease on patient-important outcomes. Disclosures Allemang: Novartis: Other: Funding for the transition navigator program; ApoPharma: Other: Funding for the transition navigator program; Sickkids Foundation: Other: Funding for the transition navigator program. Kuo:Apotex: Other: Unrestricted education grant; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Chronic Kidney Disease Is Under-Screened in SCD and Mild Albuminuria Is Associated with a Drop in Hemoglobin: A Report from the Grndad Sickle Cell Registry

Blood ◽

10.1182/blood-2019-124933 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2284-2284

Author(s):

Elizabeth Williams ◽

Elizabeth Brown ◽

Deepa Manwani ◽

Payal Desai ◽

Joshua J. Field ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Sickle Cell Disease ◽

Kidney Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Cell Disease ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

The Globin Research Network for Data and Discovery (GRNDaD) is a combined effort, from 6 US clinical sites (Baltimore, Cleveland, Columbus OH, Milwaukee, Oakland, and The Bronx) that care for people with sickle cell disease (SCD), to improve care through shared data collection and review and quality improvement. Using a single IRB-Reliant protocol, we have assembled harmonized baseline and annual data on 758 adults with sickle cell disease (41.7% male and 58.3% female, mean age 35.5), collected on a REDCap server housed at Johns Hopkins. For this study, we reviewed adherence to the 2014 NHLBI Guidelines on the management of SCD -- which recommends annual screening for chronic kidney disease (CKD) by testing for albuminuria or proteinuria in anyone over the age of 10 with sickle cell disease. To evaluate whether subjects had an annual visit in any given year we used the recording of a well visit hemoglobin. Of the 758 adults in the study 411 had at least one year of follow up data marked as completed. Among these 411 adults there were 826 distinct observations. Of these 826 observations, 137 observations among 85 subjects did not have any hemoglobin lab drawn, suggesting that they did not have a well outpatient visit during that year. Amongst the observation years, where a well hemoglobin was performed, yearly screening for albuminuria occurred in 37.4% (258/689) of annual observations. There was an association between having screening for CKD and site of care (p<.0001), with some sites having adhered to guidelines in 34.2% of observation years and others having adhered 75.9% of years. There was no association between adherence and genotype or sex. Albuminuria was associated with a clinical phenotype. A multi-variable linear mixed effects model controlling for age and gender with a randomly varying intercept based on the subject, excluding chronically transfused subjects, and stratified by sickle cell anemia (HbSS or HbSB0, SCA) or variant genotypes was used. There was a significant association in those with SCA between the presence of albuminuria between 30 and 300, level (A2) and hemoglobin. Hemoglobin levels were, on average, 0.79 g/dL lower in those with albuminuria between 30-300 when compared to those with no albuminuria (A1, P=0.005). For those with SCA and albuminuria greater than 300 (A3), the sample size was small (n=28) and hemoglobin levels were 0.61 g/dl lower compared to those without albuminuria but this was not statistically significant (p=0.12). For those with variant compound heterozygous SCD and A2 albuminuria, hemoglobin levels were not statistically significantly different from those without albuminuria. However, high-grade albuminuria (A3) was associated with hemoglobin levels which were, on average, 1.86 g/dL lower than those in group A1 (P=0.004). Interestingly, the association between reduced hemoglobin and albuminuria was seen in both variant and SCA genotypes in the context of a preserved creatinine (<1.0 mg/dL). Using a multisite registry we demonstrate the need to develop strategies to assist providers and patients with adherence to guideline based recommendations for routine screening for chronic kidney disease in adults with SCD. The early association of albuminuria with worsening anemia, even in the absence of elevated creatinine levels, suggests an added urgency to screening. The causality of the association remains unclear but emphasizes the need for longitudinally followed cohorts that might help us understand the relationship between anemia and the development of CKD. Figure Disclosures Manwani: Novartis: Consultancy; Pfizer: Consultancy; GBT: Consultancy, Research Funding. Desai:Novartis: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; University of Pittsburgh: Research Funding; Ironwood: Other: Adjudication Board; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Potomac: Speakers Bureau. Field:Ironwood: Consultancy, Research Funding; Rigel: Research Funding; Prolong: Research Funding; Incyte: Research Funding. Neumayr:La Jolla Pharmaceuticals: Research Funding; Pfizer: Consultancy, Research Funding; Bayer: Consultancy; CTD Holdings: Consultancy; CDC: Research Funding; Celgene: Research Funding; Imara: Research Funding; NHLBI: Research Funding; Sangamo: Research Funding; HRSA: Research Funding; GBT: Research Funding; Emmaus: Consultancy; Apopharma: Consultancy; Sancillo: Research Funding; Novartis: Research Funding; Bluebird Bio: Research Funding; Silarus: Research Funding; Terumo: Research Funding; PCORI: Research Funding; Doris Duke Foundation: Research Funding; Seattle Children's Research Grants: Research Funding. Clay:Novartis: Speakers Bureau. Cong:Global Blood Therapeutics: Employment, Equity Ownership. Agodoa:Global Blood Therapeutics: Employment, Equity Ownership. Hoppe:Global Blood Therapeutics: Employment, Equity Ownership. Lanzkron:PCORI: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Research Funding; Ironwood: Research Funding; HRSA: Research Funding; NIH: Research Funding. Little:Hemex Health, Inc.: Patents & Royalties; GBT: Research Funding.

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Clinical and Biomarker Predictors for Avascular Necrosis in Sickle Cell Disease

Blood ◽

10.1182/blood-2021-147829 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3091-3091

Author(s):

Michael Rabaza ◽

Maria Armila Ruiz ◽

Liana Posch ◽

Faiz Ahmed Hussain ◽

Franklin Njoku ◽

...

Keyword(s):

Risk Factors ◽

Sickle Cell Disease ◽

Board Of Directors ◽

Avascular Necrosis ◽

Sickle Cell ◽

Research Funding ◽

Medical Attention ◽

Cell Disease ◽

Advisory Committees ◽

Early Management

Abstract Introduction Sickle cell disease (SCD) affects 1 in 365 African Americans and approximately 25 million people world-wide. A common skeletal system complication is avascular necrosis (AVN), which can cause substantial pain and a reduced quality of life. While early management of AVN is focused on increasing range of motion with physical therapy and pain relief, there are no clear predictors for who is more likely to develop AVN and earlier institution of these preventive measure could help decrease disease progression. Vascular endothelial growth factor (VEGF) is a biomarker of endothelial injury and may indicate reduced vascular supply to the femoral or humeral head. Here we describe potential risk factors and biologic pathways for AVN in SCD, as understanding these may lead to improvements in future monitoring, early detection, and early intervention practices. Methods We investigated clinical and laboratory risk factors associated with AVN in a cohort of 435 SCD patients from our center. Blood samples, clinical, and laboratory data were collected at the time of enrollment during a clinic visit. Genotyping for alpha thalassemia was performed by PCR and the serum concentration of VEGF was measured by ELISA. AVN status was confirmed by review of the medical record and available imaging. We conducted a cross-sectional analysis comparing categorical and linear variables by AVN status using the chi-square and Kruskal-Wallis test, respectively. The independent association of the clinical and laboratory variables with AVN status was determined by logistic regression analysis. The initial model included variables with a P-value < 0.1 on univariate analysis and the final model was ascertained by stepwise forward and backward selection. Median values and interquartile range (IQR) are provided. Results The median age of the cohort was 32 (IQR, 24 - 43) years, 57% (250/435) were female, and 46% (198/435) were on hydroxyurea. AVN was observed in 34% (149/435) of SCD patients. SCD patients with AVN were older, had more frequent vaso-occlusive crises requiring medical attention, and had a higher body mass index (Table I) (P ≤ 0.002). We measured VEGF in 241 of the SCD patients with serum samples available at the time of enrolment. Serum VEGF concentrations trended higher in SCD patients with versus without AVN (420 vs. 359 pg/mL, respectively; P = 0.078). In the multivariate analysis model, AVN was independently associated with increased number of vaso-occlusive crises (OR 1.1, 95% CI: 1.0 - 1.14; P = 0.02), AST concentration (natural log OR 0.5, 95% CI: 0.2 - 0.9; P = 0.03), VEGF concentration (natural log OR 1.4, 95% CI: 1.0 - 1.9; P = 0.047), and tobacco use (OR 1.9, 95% CI: 0.9 - 3.7; P = 0.078). Discussion In conclusion, we demonstrate a high prevalence of AVN in an adult cohort of SCD patients. The presence of AVN was independently associated with a greater frequency of vaso-occlusive pain episodes, which may demonstrate a shared pathophysiology between AVN and vaso-occlusion that merits further investigation. We demonstrate that serum VEGF concentrations are higher in SCD patients with AVN and may be a clinical tool to identify those at high-risk and for earlier intervention for this complication. Figure 1 Figure 1. Disclosures Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Comparative Study of Haiti and Miami Cohorts of Sickle Cell Disease (CSHSCD): Methods, Accomplishments, and Implementation

Blood ◽

10.1182/blood-2021-149145 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4054-4054

Author(s):

Ofelia A. Alvarez ◽

Tally Hustace ◽

Emmeline Lerebours ◽

Nora St Victor Dely ◽

Rony Saint Fleur ◽

...

Keyword(s):

African American ◽

Sickle Cell Disease ◽

Comparative Study ◽

Newborn Screening ◽

Capacity Building ◽

Board Of Directors ◽

Isoelectric Focusing ◽

Cell Disease ◽

Advisory Committees ◽

American Ethnicity

Abstract Background: There are significant limitations in Haiti for the diagnosis and management of sickle cell disease (SCD), including the non-availability of universal newborn screening (NBS) and transcranial Doppler (TCD) ultrasound screening, and the lack of diagnostic laboratory resources, oral penicillin and hydroxyurea (HU). Methods: Beginning in September 2019, CSHSCD (R01HL149121), a 5-year NIH-sponsored observational comparative study of children with SCD from Haitian ethnicity in Miami and in Haiti compared to children of African American ethnicity with SCD, was designed to increase access to care in Haiti. The study aims are 1) to compare the incidence of SCD among newborns from Haitian and African American ethnicity in Miami, 2) to establish NBS programs for hemoglobinopathies in Haiti, and 3) to compare cohorts of children in SCD at the study sites. The participating sites are the University of Miami (UM, Miami, Florida), Hôpital Saint Damien (HSD, Tabarre, Haiti), Hôpital de l'Université d'Etat d'Haïti (HUEH, Port-au-Prince, Haiti), Hôpital Universitaire Justinien (HUJ, Cap Haitien, Haiti), and Hôpital Sacré Coeur (HSC, Milot, Haiti). HUJ and HSC use two NBS screening methods (isoelectric focusing and Sickle SCAN rapid test) and HSD and HUEH use isoelectric focusing only. CSHSCD supplies penicillin and HU and trains TCD examiners to implement stroke risk screening. Data are collected in REDCap. Results: During the first 2 years and despite the COVID-19 pandemic, we established NBS sites with a cohesive network of physicians and nurses trained in the care of children with SCD in Haiti. This capacity building will support sustainability of the program. We successfully identified at least 15 new cases of SCD via newborn screening, trained six TCD examiners, and enrolled 130 children with SCD in follow up, providing them with penicillin prophylaxis and hydroxyurea for severe cases according to local protocols . Implementation activities which have helped are close communications between the investigators, monthly Zoom meetings to coordinate efforts with enrollment updates every month, the availability of rapid tests (Sickle SCAN and Gazelle miniature cellulose acetate electrophoresis) for the diagnosis of SCD, especially when there is no laboratory equipment on site. Implementation challenges we have faced are mostly two. The first is the timely completion of DUNS and SAM registration for the two public hospitals, with one site achieving this after 9 months and the other site taking 18 months to complete. The reasons for the delay are the inability for the UM site to direct these efforts, following strict rules, and the Haitian hospital officers' lack of familiarity with website requirements. We were able to achieve these registrations with the assistance of one Haitian study staff who is very acquainted with internet navigation and became familiarized with requirements. Outsourcing materials to Haiti is another major challenge, with either gaps in the delivery of supplies because of multiple steps involved in ordering and shipping or with delays in releasing equipment once it is at the Port-au-Prince customs, resulting in gaps in NBS in one of the sites for 8 weeks. We have minimized these issues by opening a one-year ticket to order materials from the different companies involved. Also, Haiti's lack of infrastructure, available materials and medications, and political instability limit health care delivery. Conclusion: Since its inception, we have achieved major milestones, including capacity building and implementation of NBS, TCD training, and enrollment of children with SCD into the prospective cohorts despite the current COVID-19 pandemic. Material outsourcing challenges have been the major implementation problem we have faced due to systemic factors. We anticipate that these factors will be corrected or minimized as we have learned how to handle them. These problems were expected as part of conducting an international study in a low-resource setting. Acknowledgment: We acknowledge NHLBI for supporting this work. Disclosures Alvarez: Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; GBT: Membership on an entity's Board of Directors or advisory committees. Romano: Genentech: Research Funding; Vycor: Current holder of individual stocks in a privately-held company; NovaVision: Consultancy.

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Crizanlizumab Therapy Is Associated with Lower Levels of Circulating Extracellular Vesicles in Sickle Cell Disease Patients

Blood ◽

10.1182/blood-2021-153377 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 955-955

Author(s):

Cristiane Maria de Souza ◽

Carolina Lanaro ◽

Irene Pereira dos Santos ◽

Oladele Olatunya ◽

Sara T Olalla Saad ◽

...

Keyword(s):

Endothelial Cells ◽

Sickle Cell Disease ◽

Board Of Directors ◽

Extracellular Vesicles ◽

Sickle Cell ◽

Treated Group ◽

Clinical Severity ◽

Cell Disease ◽

Advisory Committees ◽

Activated Platelets

Abstract Extracellular vesicles (EVs) are submicron structures released in blood circulation by different cell types which have been found to be increased in sickle cell disease (SCD) and are associated with clinical complications. The most abundant EVs in SCD patients derive from platelets, endothelial cells, and red blood cells (RBCs) and EVs have been explored as biomarkers of clinical severity. Crizanlizumab is a monoclonal antibody against P-selectin, an adhesion molecule expressed in activated platelets and endothelial cells. P-selectin facilitates the formation of heterocellular aggregates and is implicated in the pathophysiology of vaso-occlusive episodes (VOEs) in SCD. This study aimed to investigate the circulating levels of EVs in patients with SCD on standard of care or treated with crizanlizumab. We collected peripheral blood samples from 20 adults with SCD (Non treated group: 7 patients on hydroxyurea treatment and 7 without it. Treated group: 6 patients undergoing treatment with crizanlizumab in combination with hydroxyurea). Patients received the last dose of crizanlizumab at least a month prior to the study. EVs were identified by lactadherin+calcein stain and quantified by flow cytometry to determine the immunophenotype of their parent cell (platelet, endothelial cell, and RBC, with CD41+; CD146+/CD45-; CD235+, respectively). EV quantification was calculated in number per ml of blood as previously described by our group (Olatunya et al., 2019). We found that patients on crizanlizumab had lower total circulating EV counts than patients not receiving the drug (62.670.000,00 ± 15.600.000,00 vs 13.100.000,00 ± 3.513.000,00/mL, respectively, p=0,0076). The difference was statistically significant in platelet-derived EVs levels (5.397.000,00 ± 953.875,00 vs 2.413.000,00 ± 745.165,00/mL, p=0,0169), but not in endothelium-derived or RBC-derived EVs (345714 ± 101817 vs 220000 ± 64291, and 2.189.000,00 ± 1.648.000,00 vs 1.013.000,00 ± 572775, respectively). Crizanlizumab therapy has been shown to reduce the incidence of VOEs in SCD. EVs have been recognized as bio-effectors involved in VOEs, contributing to a hypercoagulable state, chronic inflammation, and endothelial damage. Our findings show an association between the use of crizanlizumab and lower EV levels, particularly of the platelet-derived type. While the anti-P-selectin activity of crizanlizumab could be expected to help remove platelets from circulation, clinical studies have not reported a reduction in platelet counts in patients treated with crizanlizumab. Therefore, we speculate that crizanlizumab may decrease the release of EV by activated platelets, reduce platelet activation, or contribute to EV removal from circulation. Our findings suggest that crizanlizumab therapy may modulate EV levels in the plasma of SCD patients and provide, for the first time, data to support exploring the use of extracellular vesicles as biomarkers to monitor the clinical response to this drug in patients. Further studies on EV expression of P-selectin and how crizanlizumab interacts with EVs and platelets may help clarify this particular effect of this drug. Disclosures Benites: Novartis: Honoraria. Fertrin: Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Costa: Novartis: Consultancy.

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Sex Based Differences in Sickle Cell Disease

Blood ◽

10.1182/blood-2020-140896 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 37-37

Author(s):

Rita V Masese ◽

Dominique Bulgin ◽

Mitchell Knisely ◽

Liliana Preiss ◽

Eleanor Stevenson ◽

...

Keyword(s):

Sickle Cell Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Categorical Variables ◽

Continuous Variables ◽

Cell Disease ◽

Advisory Committees ◽

Blood Institute ◽

National Heart Lung

Introduction Sickle cell disease (SCD) is the most common inherited blood disorders in the United States. The disease predominantly affects African Americans with 1 out of every 365 individuals born with SCD. The disease is characterized by vascular inflammation and vaso-occlusion leading to numerous complications and multi-organ dysfunction. Previous studies have shown women with SCD tend to outlive their male counterparts. Other than the increased life expectancy, sex-based clinical outcome differences in SCD remain largely unknown. To better characterize sex-based differences in SCD, we assessed sociodemographic characteristics, pain, treatment characteristics, laboratory measures and complications among males and females currently enrolled in the Sickle Cell Disease Implementation Consortium (SCDIC) registry. Methods The SCDIC consists of eight academic and comprehensive SCD centers, and one data-coordinating center that received funding from the National Heart Lung and Blood Institute to improve outcomes for individuals with SCD. Participants were eligible for the enrollment in the SCDIC registry if they were 15 to 45 years of age and had a confirmed diagnosis of SCD. Participants were excluded if they had sickle cell trait or had a successful bone marrow transplant. Enrolled participants completed surveys. Data were also abstracted from the participants' medical records. Data were entered into a REDCap database and analyzed using SAS version 9.4 (SAS Institute; Cary, NC). Categorical variables were presented as frequencies and percentages, continuous variables were presented as medians and interquartile ranges (IQR) or means and standard deviations. Categorical variables were analyzed using Chi-Square or Fisher exact tests when appropriate. Continuous variables were compared using the Mann-Whitney U test or independent sample t-tests depending on the distribution. A two-sided p-value less than 0.05 was deemed significant. Results A total of 2,124 participants were included in the study. The mean (SD) age of our participants was 27.8 (7.9) years. Almost all (95.6%) were Africa American, female (56%) and had hemoglobin SS (68.2%) SCD genotype. More males (55.4 % vs. 44.6%, p <0.0001) were taking hydroxyurea. Females had significantly worse reports of pain frequency and severity (p=0.0002 and <0.0001 respectively), more vaso-occlusive episodes (p=0.01) and a higher occurrence of 3 or more hospital admissions in the past year (30.9 % vs. 25.5, p= 0.03). Males had significantly more skin ulcers and respiratory, musculoskeletal, genitourinary and cardiovascular complications while females had more anxiety, depression and autoimmune conditions. Males also had significantly higher creatinine, blood urea nitrogen, albumin and liver enzymes (alkaline phosphatase, aspartate and alanine aminotransferases). Females had higher fetal hemoglobin levels with and without hydroxyurea use. There were no statistical differences in ethnicity, marital and employment status. Conclusion Key differences in SCD presentation and occurrence of complications exist among males and females. Females had higher rates of depression and anxiety while males had more chronic end-organ complications that are life threatening. Our findings emphasize the need for stratification of data analysis by sex in future SCD studies. Disclosures Hankins: Global Blood Therapeutics: Consultancy, Research Funding; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; LINKS Incorporate Foundation: Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria; MJH Life Sciences: Consultancy, Patents & Royalties; UptoDate: Consultancy; Novartis: Research Funding. Treadwell:UpToDate: Honoraria; Global Blood Therapeutics: Consultancy. King:Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company; RiverVest: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bioline: Consultancy; Novimmune: Research Funding; Amphivena Therapeutics: Research Funding. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Kanter:bluebird bio, inc: Consultancy, Honoraria; SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Sanofi: Consultancy; Medscape: Honoraria; Guidepoint Global: Honoraria; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees. Glassberg:Eli Lilly and Company: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Consultancy. Shah:Bluebird Bio: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy; Alexion: Speakers Bureau.

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Improvement in the Clinical Global Impression of Change with Voxelotor in Patients with Sickle Cell Disease in the Phase 3 HOPE Trial

Blood ◽

10.1182/blood-2020-137121 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 5-6

Author(s):

Wally R Smith ◽

Jane S. Hankins ◽

Miguel R Abboud ◽

Ze Cong ◽

Jonathan Sorof ◽

...

Keyword(s):

Sickle Cell Disease ◽

Board Of Directors ◽

Clinical Global Impression ◽

Research Funding ◽

Cell Disease ◽

Publicly Traded ◽

Advisory Committees ◽

Global Impression Of Change ◽

Study Participants ◽

The Impact

Background: Patients with sickle cell disease (SCD) experience varied salient symptoms that impact their health-related quality of life, which incorporates illness severity, their level of distress and other aspects of impairment, and the impact of the illness on functional status. SCD symptoms may begin at an early age, and their severity varies over time and between patients. Although detection of changes in patients' self-assessed symptoms may be obfuscated by their lifelong symptoms, treating physicians with SCD expertise may be able to detect changes in a patient's status given their experience in treating the diverse symptoms across multiple patients. We evaluated the longitudinal impact of voxelotor (Oxbryta®) in the HOPE study using the single-item Clinical Global Impression of Change (CGI-C), a validated clinician-reported outcome analogous to the commonly used Patient Global Impression of Change (PGI-C), which provides expert clinical impressions that transcend symptom checklists. Methods: In the randomized, placebo-controlled, double-blinded HOPE study, participants with SCD aged 12 to 65 years were randomized to receive voxelotor (1500 mg or 900 mg dose administered orally, once daily) or placebo. Study participants had a hemoglobin (Hb) level 5.5 to 10.5 g/dL at enrollment and 1 to 10 vaso-occlusive crises in the past 12 months at screening. Clinicians were blinded to treatment assignment and to all central laboratory measures (eg, hematological parameters) throughout the 72-week study period. Clinicians rated the CGI-C at 24 and 72 weeks from baseline. CGI-C ratings used a 7-point scale ("very much improved," "moderately improved," "minimally improved," "no change," "minimally worse," "moderately worse," and "very much worse"). CGI-C outcomes were stratified by baseline Hb levels and baseline markers of hemolysis to identify measures predictive of assessment outcomes. Results: Trends of improvement from baseline in overall clinical status with voxelotor 1500 mg, as assessed by CGI-C scores, were observed as early as week 24. At week 72, patients receiving voxelotor 1500 mg were more often rated by the clinician as "very much improved" or "moderately improved" (74%; 39 of 53) compared with those who received placebo (47%; 24 of 51) (P<0.01, Figure 1). CGI-C score improvement was consistently greater in participants treated with voxelotor compared with placebo regardless of baseline Hb. Greater proportions of participants were rated "very much improved" or "moderately improved" with voxelotor 1500 mg than placebo regardless of baseline hemolysis markers (indirect bilirubin, percentage reticulocytes, absolute reticulocyte count). Conclusions: Treatment with voxelotor 1500 mg resulted in improved clinician-reported patient outcomes, as assessed using the CGI-C. Greater proportions of participants were rated "very much improved" or "moderately improved" regardless of baseline Hb levels and baseline markers of hemolysis. The CGI provides an overall clinician-determined summary measure that takes all available information into account, including the patient's history, psychosocial circumstances, symptoms, and behavior, as well as the impact of symptoms on the patient's ability to function. Therefore, a tool that provides a holistic assessment of a patient's well-being may be complementary in capturing changes in a patient's status, considering the substantial interpatient and intrapatient variability in SCD symptomatology. CGI-C assessments are being included in ongoing studies of voxelotor. Disclosures Smith: Emmaeus Pharmaceuticals, Inc.: Consultancy; Novartis, Inc.: Consultancy, Other: Investigator, Research Funding; Global Blood Therapeutics, Inc.: Consultancy, Research Funding; Shire, Inc.: Other: Investigator, Research Funding; NHLBI: Research Funding; Patient-Centered Outcomes Research Institute: Other: Investigator, Research Funding; Health Resources and Services Administration: Other: Investigator, Research Funding; Incyte: Other: Investigator; Pfizer: Consultancy; Ironwood: Consultancy; Novo Nordisk: Consultancy; Imara: Research Funding; Shire: Research Funding; GlycoMimetics, Inc.: Consultancy. Hankins:American Society of Pediatric Hematology/Oncology: Honoraria; UptoDate: Consultancy; Novartis: Research Funding; MJH Life Sciences: Consultancy, Patents & Royalties; LINKS Incorporate Foundation: Research Funding; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding. Abboud:Novartis: Consultancy, Honoraria, Research Funding; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Crispr Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Travel support; Eli Lilly: Research Funding; Modus Pharmaceuticals: Research Funding. Cong:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sorof:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gray:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Hoppe:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Telfer:Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Terumo: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Honoraria, Research Funding; ApoPharma: Membership on an entity's Board of Directors or advisory committees.

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Sickle-Cell Disease Patients' Attitudes Towards Their Treatment with Hydroxycarbamide

Blood ◽

10.1182/blood-2019-125673 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1013-1013

Author(s):

Frédéric Galactéros ◽

Ersi Voskaridou ◽

Anoosha Habibi ◽

Giovanna Cannas ◽

Laure Joseph ◽

...

Keyword(s):

Sickle Cell Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Fetal Hemoglobin ◽

Treatment Discontinuation ◽

Cell Disease ◽

Advisory Committees

Hydroxyurea (HU) is approved in the EU and USA for prevention of vaso-occlusive crises (VOC) including acute chest syndromes (ACS) in patients over 2 years with sickle-cell disease (SCD). The major benefits of HU in SCD are directly related to its abilities to increase HbF, decrease sickling of red blood cells and hemolysis, leading to reduction of vaso-occlusive episodes, need for blood transfusions and consequently reduction of morbidity and mortality. Adherence to the treatment is paramount for effectiveness, but in spite of proven benefits, barriers to adherence persist.[1] ESCORT-HU study (European Sickle Cell Disease COhoRT - HydroxyUrea), is a multicentric, prospective, non-interventional European study designed to evaluate the safety profile of HU in real life. Patients were enrolled from January 2009 to June 2017 with a follow-up of up to 10 years. All interruptions and resumptions of HU treatment exceeding 15 days were recorded in this study. We hereby present the analysis of the group of patients who self-discontinued HU at least once during the study before informing their caregiver, with a view to identify potential barriers to long-term adherence. In total, 1906 patients were enrolled in ESCORT-HU from 63 centers in France, Germany, Greece and Italy. Of these, 619 patients (32%) stopped HU for over 15 days at least once, and around a third (11% of all patients) were due to patient's will. The mean duration of HU treatment before the first discontinuation was 4.8 ± 5.1 years. Data are summarized in table 1. Compared to the rest of the cohort, the 'treatment discontinuation' group had similar distribution by gender and indication for HU prescription, but a higher proportion of adults stopped HU more than 15 days. It is notable that the proportion of patients with SC genotype was higher in the 'treatment discontinuation' group (4.5% vs 1.7%). The patients in the 'treatment discontinuation' group had more frequent SCD symptoms before enrolment in the study (table 2). Hematological and clinical improvement compared to the baseline was observed in both groups. However, average mean Corpuscular Volume (MCV) and Fetal Hemoglobin percentage (HbF%) were lower and mean percentages of patients with SCD symptoms were higher over the three years of follow-up in the 'treatment discontinuation' group, suggesting that HU daily dose was insufficient (table 2). Sixty patients have no treatment resumption date reported which suggest a permanent interruption of their treatment. Among them 32% preferred to switch to another HU medicinal product and 13% have safety issue (table 3). Understanding and managing self-discontinuation of HU before taking medical advice is challenging for the physician. It is tempting to speculate that it may be due, at least in part, to lack of effectiveness potentially due to an underdosage of the treatment. Resistance to the treatment may also be suggested based on past literature data revealing a great variability in the response (determined by HbF%) to HU therapy. There is evidence that genetic modifiers affect individual response to HU.[2],[3] Finally, weariness from long-term use may also explain the patient's wish to discontinue HU. But treatment at optimal effective should be the primary goal of caregivers. [1]Smaldone A., Manwani D., Green NS, Greater number of perceived barriers to hydroxyurea associated with poorer health-related quality of life in youth with sickle cell disease, Pediatr Blood Cancer. 2019 [2] Steinberg MH, Voskaridou E, Kutlar A, Loukopoulos D, Koshy M, et al. (2003). Concordant fetal hemoglobin response to hydroxyurea in siblings with sickle cell disease. Am J Hematol 72: 121-126 [3] Ware RE, Despotovic JM, Mortier NA, Flanagan JM, He J, et al. (2011) Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia. Blood 118: 4985-4991 Disclosures Galactéros: Addmedica: Membership on an entity's Board of Directors or advisory committees. Voskaridou:Celgene Corporation: Consultancy, Research Funding; Protagonist: Research Funding; Genesis: Consultancy, Research Funding; Acceleron: Consultancy, Research Funding; Addmedica: Membership on an entity's Board of Directors or advisory committees. Cannas:Addmedica: Membership on an entity's Board of Directors or advisory committees.

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"Prevalence and Outcome of Avascular Necrosis of the Hip (AVN) Among Young Omani Patients with Sickle Cell Disease"

Blood ◽

10.1182/blood-2019-127875 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3577-3577

Author(s):

Iman Al Fadhali ◽

Farah Al-Kindy ◽

Naema Alshibli ◽

Salam Alkindi ◽

Murtadha Al-Khabori ◽

...

Keyword(s):

Sickle Cell Disease ◽

Board Of Directors ◽

Avascular Necrosis ◽

Sickle Cell ◽

Tertiary Care ◽

University Hospital ◽

Average Dose ◽

Cell Disease ◽

Advisory Committees ◽

Female Ratio

Background: Sickle cell disease is a common hemaglopinapthy worldwide and in Oman. Avascular necrosis (AVN) of the hip causes significant morbidity to patients with sickle cell disease and has a profound impact on their quality of life. This study aims to identify the prevalence and outcome of AVN among young Omani patients with sickle cell disease. Methods: The is a cross sectional study done in the main tertiary care and referral facility in Oman, Sultan Qaboos University Hospital. Out of 3000 registered patients 85 patients found to have clinical and radiological proven AVN, between June 2017-January 2019. Data obtained included demographics, the affected joint, uni or bilateral), radiological staging by FICAT (MRI), hydroxyurea use, dose and duration as well as laboratory data at time of diagnosis. Results: The prevalence of AVN among SCD Omani children and young adults is 2.8 %. Their age ranges between 5-25 (Mean 14.6 +3.4). Male to female ratio was 1.6:1. Based on FICAT system score, most of the cases (82%) are AVN grade 3 and above at diagnosis. Thirty-six patients (42%) were diagnosed to have stage IV AVN. Regarding the hydroxyurea use, 43 patients (50.6%) were already started on HU before the development of AVN. Their mean duration of HU use was 5.3 years, with an average dose of 15.7 mg/kg/day. Fifteen patients developed AVN and were started on HU as part of their management. The follow up MRI of 4 of them showed improvement of their AVN stage (from 4 to 2). Fifteen patients (17.6%) underwent joint replacement because of chronic pain and disability and almost half of them (7 patients) were on hydroxyurea. Conclusion: Prevalence of AVN in young patients with SCD in the main tertiary care referral facility in Oman is 2.8% which is less than the internationally reported. Patients are diagnosed at later stages (3 and above) indicating a possibility of underdiagnosis of asymptomatic stage one and 2 patients. Hydroxyurea use has improved the severity of the AVN in few patients. Disclosures Al-Khabori: SOBI: Honoraria; AstraZeneca: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Shire (Takeda): Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; NovoNardisk: Membership on an entity's Board of Directors or advisory committees. Wali:Sultan Qaboos University Hospital: Employment.

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Effects of BCL11A Shmir-Induced Post-Transcriptional Silencing on Distributions of HbF in Single-RBCs and Reticulocytes

Blood ◽

10.1182/blood-2021-150186 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 967-967

Author(s):

Nicolas Hebert ◽

Erica B. Esrick ◽

Myriam Armant ◽

Christian Brendel ◽

Marioara Felicia Ciuculescu ◽

...

Keyword(s):

Sickle Cell Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Insertion Site ◽

Fetal Hemoglobin ◽

Fold Increase ◽

Advisory Board ◽

Cell Disease ◽

Advisory Committees

Abstract NH and EE equally contributed. ADW and PB co-signed. The expression of fetal hemoglobin (HbF) is one of the main targets of sickle cell disease treatment, as it inhibits the polymerization of hemoglobin S. The hypothesis of an inhibitory threshold of HbF per red blood cell (RBC) has been suggested, 1 although not well defined, as the overall percentage of HbF does not reflect the heterogeneous distribution of HbF per cell. Likewise, the qualitative analysis of RBCs containing HbF, called F cells, is neither reproducible nor clinically interpretable, due to low expression. 2 We have developed a technique for measuring the amount of HbF per cell, to determine thresholds of HbF expression per RBC correlated with clinical and biological effects. 2 Among genes controlling its expression, BCL11A has a major repressive effect on the expression of gamma globin/HbF during the fetal to adult hemoglobin switch. Post-transcriptional silencing of BCL11A, using lentivirus expression of a shRNA embedded in a microRNA architecture (shmiR) to re-activate γ-globin expression, is safe and demonstrates high levels of %HbF in a pilot clinical study (NCT 03282656). 3 Here, we show the quantitative measurement of HbF per RBC and reticulocyte. Methods: During patient follow-up, HbF quantification per single cell RBC was performed using a fluorescent HbF antibody. 2 Addition of an anti-CD71 fluorescent antibody allowed selection of reticulocyte sub-populations for determining their HbF content. Fold-increase in percentage of RBC versus percentage of reticulocyte were calculated. Kinetics of HbF/RBC and HbF/Reticulocyte were modeled using mixed effects polynomial linear regression to account for the correlation between repeated data over time. Results: With a median follow-up of 15 months [12-20] after gene transfer, figure 1 shows the mathematical modeling of single-RBC HbF measurement representing RBC percentage containing at least 2, 4, 6, 8 and 10 pg of HbF. Percentage of RBC above each threshold was higher compared to 14 hydroxyurea treated patients for 6 months. Figure 2 shows fold increase between reticulocytes and RBCs with same thresholds of HbF/cell. For low thresholds, RBCs were found in same percentage as reticulocytes whereas RBCs containing increasing levels of HbF were found in higher percentage than reticulocytes, until 6pg/cell showing a clear selective advantage for red cells with a threshold ≥ 6pg/cell of HbF. Figure 3 shows different kinetics of HbF increase according to two different transduction strategies with 2 enhancers in patients 2-4 compared to one enhancer in patients 6-8. Conclusion: BCL11A down-regulation in six clinical trial subjects was associated with an in vivo selection process RBCs with ≥ 6pg HbF per cell attained with different engraftment kinetics, depending on transduction processes, and ultimately stable high level and broadly distributed HbF. 1 Steinberg MH, Chui DH, Dover GJ, Sebastiani P, Alsultan A. Fetal hemoglobin in sickle cell anemia: a glass half full? Blood. 2014 Jan 23;123(4):481-5. 2 Hebert N, Rakotoson MG, Bodivit G, et al. Individual red blood cell fetal hemoglobin quantification allows to determine protective thresholds in sickle cell disease. Am. J. Hematol. 3 Esrick EB, Lehmann LE, Biffi A, et al. Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease. N. Engl. J. Med. 2021;384(3):205-215. Figure 1 Figure 1. Disclosures Esrick: bluebird bio: Consultancy. Audureau: GBT: Honoraria. Higgins: Sebia, Inc.: Honoraria; Danaher Diagnostics: Consultancy. Williams: BioMarin: Membership on an entity's Board of Directors or advisory committees, Other: Insertion Site Advisory Board; Geneception: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; Emerging Therapy Solutions: Membership on an entity's Board of Directors or advisory committees, Other: Chief Scientific Chair; Beam Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; Alerion Biosciences: Other: Co-founder (now licensed to Avro Bio, potential for future milestones/royalties); Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee, Novartis ETB115E2201 (eltrombopag in aplastic anemia). Advisory fees donated to NAPAAC.; Orchard Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Membership on a safety advisory board (SAB): SAB position ended 05/20/2021. Co-founder , Patents & Royalties: Potential for future royalty/milestone income, X-SCID. Provided GMP vector for clinical trial, Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Other: Insertion Site Analysis Advisory Board, Patents & Royalties: BCH licensed certain IP relevant to hemoglobinopathies to bluebird bio. The current license includes the potential for future royalty/milestone income. Bluebird has indicated they will not pursue this as a clinical program and BCH is negotiating return of, Research Funding. Bartolucci: AGIOS: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Jazz Pharma: Other: Lecture fees; Emmaus: Consultancy; Addmedica: Consultancy, Other: Lecture fees, Research Funding; INNOVHEM: Other: Co-founder; Hemanext: Consultancy; GBT: Consultancy; Bluebird: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy; Fabre Foundation: Research Funding.

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