Limited Access to Transcranial Doppler Screening and Stroke Prevention for Children with Sickle Cell Disease in Europe: Results of a Multinational Eurobloodnet Survey

Abstract Background: Children with sickle cell disease (SCD) are at increased risk of cerebrovascular events such as stroke, silent infarcts and neurocognitive impairment. The role of Transcranial Doppler ultrasound scanning (TCD) to identify sickle cell anemia (SCA) children at high risk of stroke is well established. Adam et al in 1998 recommended those with abnormal cerebrovascular flow velocities are offered prophylactic blood transfusion therapy to prevent stroke between ages 2 to 16 years. Therefore, TCD screening for stroke prevention in now is a mandatory in all guidelines for the management of children with SCA. However, there is still no uniform implementation of the program globally and in European countries (Rees 2016). Moreover, the information available on the quality of the TCD screening is limited to educational experiences in a few countries (Inusa 2019) but to evaluation of stroke prevention programs has been performed in Europe. As more disease modifying therapies become available for children with SCD, it is mandatory to know TCD availability, screening practices, and real-world data on stroke prevention in Europe. EuroBloodNet is the European Reference Network (ERN) on rare Hematological Disorders, one of the 24 ERN established by the European Union to improve care of patients with rare disorders in Europe. EuroBloodNet's main goal is to improve the healthcare and overall quality of life of patients with a Rare Hematological Disease by: 1) Improving equal access to highly specialized healthcare delivery through a multidisciplinary patient centered approach; 2) Enhancing the best practices in prevention, diagnosis and safe clinical care across Europe based on promotion of evidence based guidelines. We wanted to assess the state of the art of TCD screening and stroke prevention programs in European Expert Centers. Methods: An online survey was developed by SCD experts in 5 European countries and sent to all Representatives of the Health Care Providers (HCP) and the Red Cell Disorder representatives in each HCP within the EuroBloodNet network, as well as to National Representatives of Scientific Societies within European Countries. Items in the survey are listed in Table 1. Results 81 hematologists or pediatricians from 77 centers in 16 European countries responded to the survey (14/16 in Western Europe); 39/77 (51%) were EuroBloodNet Expert centers, 14/77 (18%) were under evaluation as being recognized; 67/77 specified their expertise: 24% were pediatric, 3% adult, 58% both; 12 centers had >200 patients in the age range 1-16 years. 36% Physicians reported not having a dedicated TCD/TCDi service for children with SCD so exams had to be performed by cardiologists (10%), general radiologists (28%), TCD is not performed (31%), or patients have to be sent in another center (31%). 74% reported requesting annual TCD for their patients, but to the question "What percentage of your patients receives annual TCD" only 28% confirmed that all their patients managed to actually receive annual TCD, due to lack of trained staff (43%), lack of TCD instruments (11%), refusal of patients due to logistical difficulties (22%) (i.e TCD in another city), lack of funds for dedicated staff or equipment (11%), or other reasons. Only 74% of hematologists were aware of the protocol in use at their center by the staff performing TCD; the STOP criteria were applied by 64% of the physicians, mainly due non evaluation of the Internal Carotid Artery. The extracranial part of the carotid artery was evaluated only in 30% of the respondents. In case of abnormal/conditional TCD results, the approach varies and is not uniform across centers. Conclusions Our data show that less than 30% of children with SCD followed in European Centers receive annual TCD according to recognized guidelines. This first multinational European survey allowed the identification of issues related to the lack of access to TCD, lack of trained staff, lack of adequate protocols for implementation of TCD and treatment afterwards, which will need to be addressed through dedicated actions. Figure 1 Figure 1. Disclosures Casale: Novartis Farma SpA: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mañú Pereira: Novartis: Research Funding; Agios Pharmaceuticals: Research Funding. de Montalembert: Vertex: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Membership on an entity's Board of Directors or advisory committees; Addmedica: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Colombatti: Global Blood Therapeutics: Research Funding; Addmedica: Consultancy; Forma Therapeutics: Consultancy; Novartis: Consultancy; NovoNordisk: Consultancy; BlueBirdBio: Consultancy; Global Blood Therapeutics: Consultancy; BlueBirdBio: Research Funding.

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Children in the United States with Sickle Cell Disease Experience Greater Educational Burden Than Those Living in Low/Middle Income and Other High-Income Countries

Blood ◽

10.1182/blood-2021-146566 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3106-3106

Author(s):

Fuad El Rassi ◽

John James ◽

Biree Andemariam ◽

Beverley Francis-Gibson ◽

Caterina P Minniti ◽

...

Keyword(s):

Sickle Cell Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Cell Disease ◽

Advisory Committees ◽

Middle Income ◽

Global Impact ◽

The Us

Abstract Introduction: The Sickle Cell World Assessment Survey (SWAY) was a cross-sectional survey to assess the global impact and treatment of sickle cell disease (SCD). Complications of SCD can lead to significant negative effects on patient (pt) quality of life. Recurrent vaso-occlusive crises (VOCs) are one of the most common SCD complications and can lead to poor quality of life and chronic organ damage. SCD manifestations can start as early as the first year of life. The implications of SCD on a child's life can be far reaching and may affect education, the global impact of which has not been well described. Here, we assess data from SWAY to better understand the impact of SCD on education among pediatric pts in the US vs other high-income countries (HIC) and low/middle-income countries (LMIC). Methods: SWAY included individuals aged ≥6 years with a diagnosis of SCD. The survey was completed by proxy (parent/caregiver/guardian) for pts aged 6-11 years and could be optionally self-completed by pts aged ≥12 years. The survey consisted of 7 ratings-based (Likert scale) questions focused on education, where a score of 5, 6, or 7 indicated increasing levels of agreement. Pediatric pts were defined as those aged <18 years. Per the World Bank definition, HIC were defined as having a gross national income per capita of ≥US$12,536; LMIC represented all remaining countries. SWAY was not designed to assess treatment outcomes; all analyses are descriptive. Age groups were not matched, and pts were not followed up over time. Results: Among the 769 pediatric pts participating in SWAY, there were 77 US respondents to the educational survey (mean age, 12 y), 200 HIC respondents (mean age, 13 y), and 492 LMIC respondents (mean age, 12 y, [one respondent did not provide an age]). Pediatric pts in all groups reported that SCD adversely impacted their education. Of the US respondents, 51%, 45%, and 52% agreed that SCD negatively impacted performance on school tests, overall performance at school, and school attendance, respectively. This was a higher rate of agreement for these statements than that reported by pediatric pts from other HIC (25%, 23%, 36%) and LMIC (37%, 41%, 50%). The US respondents also agreed that SCD negatively affected performance on homework (45%), caused them to repeat a year or class (42%), lowered interest in school (36%), and limited educational progression (35%). Again, this was a higher rate of agreement than that reported by pediatric pts from other HIC (26%, 14%, 19%, 20%) and LMIC (37%, 32%, 34%, 29%). Interestingly, the largest differences in reported school impact occurred between the US and HIC, where the US respondents showed nearly two-fold higher agreement for all statements except for reduced attendance. Conversely, there were only minor differences between respondents from the US and LMIC. Full results are presented in the Figure. Conclusions: A higher proportion of pediatric pts in the US reported a negative impact of SCD on schooling compared with those in HIC and LMIC. These results were unexpected but align strongly with the emerging evidence that social determinants prevalent in the US lends itself away from the benefits of living in a resource-rich nation. Figure 1 Figure 1. Disclosures James: GBT: Honoraria; Novartis: Honoraria. Francis-Gibson: Global Alliance of SCD Organizations: Membership on an entity's Board of Directors or advisory committees; Sickle Cell Disease Association of America: Current Employment; Alliance for Regenerative Medicine Foundation for Cell and Gene Medicine: Membership on an entity's Board of Directors or advisory committees; ASH: 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. Minniti: GBT: Consultancy, Research Funding; Novartis: Consultancy, Honoraria; NovoNordisk: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Paulose: Novartis Pharmaceuticals Corporation: Current Employment. Bailey: Novartis Pharmaceuticals: Other: I am an employee of Adelphi Real World, which received payment from Novartis Pharmaceuticals for this research. Rajkovic-Hooley: Novartis Pharmaceuticals: Other: I am an employee of Adelphi Real World, which received payment from Novartis Pharmaceuticals for this research. Osunkwo: Forma Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Health and Services Administration: Research Funding; Patient Centered Outcomes Research Instituted: Research Funding; Micella Biopharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Chiesi: Consultancy; Emmaus: Consultancy; Cyclerion: Consultancy; Acceleron: Consultancy; Global Blood Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Terumo: Consultancy.

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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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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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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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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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Risk of Hospitalization for Vaso-Occlusive Episode in Patients with Sickle Cell Disease after out-Patient Exposure to Systemic Corticosteroids

Blood ◽

10.1182/blood-2021-151307 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2048-2048

Author(s):

Ondine Walter ◽

Pierre Cougoul ◽

Julien Maquet ◽

Pablo Bartolucci ◽

Maryse Lapeyre-Mestre ◽

...

Keyword(s):

Sickle Cell Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Cell Disease ◽

National Health Insurance System ◽

Advisory Committees ◽

Systemic Corticosteroids ◽

Increased Risk ◽

Case Period

Abstract Introduction : Sickle cell disease (SCD) is an inherited disorder which affects 300,000 newborns per year. Vaso-occlusive episodes (VOEs) cause an important morbi-mortality and a decreased quality of life in patients with SCD. Some risk factors of VOE are well known, like infection, cold exposure, stress, pulmonary diseases and dehydration. Exposure to systemic corticosteroids has been suspected to increase the occurrence of VOEs in few case reports or series. However, no comparative study has been conducted to demonstrate this risk which is still debated, resulting in discrepancies among guidelines on SCD management. This study aimed to assess the risk of hospitalization for VOE associated with out-hospital exposure to systemic corticosteroids in patients with SCD in France. Methods : Data source was the French national health insurance system database, named SNDS (Système National des Données de Santé) between 2010 and 2018. The SNDS links sociodemographic, out- and in-hospital data for the entire French population (>66 million inhabitants). The study population consisted in all patients with SCD with at least one hospitalization for VOE during the study period, identified with a primary discharge diagnosis of VOE (D57.0 code of the international classification of disease, 10 th version; positive predictive value: 98.6%). All genotypes (homozygous SS-SCD and double-heterozygous SCD) were included. Because we assessed out-hospital exposure to corticosteroids, patients hospitalized during the three months before the first VOE were excluded. We performed a case-case-time-control study (Figure 1). This self-controlled design results in self-adjustment for time-independent confounders, including genotype. The outcome was the first hospitalization for VOE. The exposure to oral and injectable corticosteroids, identified using out-hospital reimbursement data, was assessed during a case period (28 days before the outcome) compared to the exposure during a control period (28 days, starting 84 days before the outcome). The same comparison was made among future cases (matched patients hospitalized for VOE the year after the given case), in order to adjust for the trend of exposure to corticosteroids (calendar variations of corticosteroid exposure). Results : Overall, 5,151 cases of VOEs were included in the main analysis. Median age at first VOE was 16.9 years; 317 (6.2%) patients were exposed to corticosteroids during the case period. In the main analysis, corticosteroid exposure was significantly associated with the occurrence of hospitalizations for VOEs: adjusted Odds Ratio (aOR): 3.81, 95% confidence interval (95% CI): 2.44 to 5.61. In patients exposed to hydroxyurea, the aOR was 2.61, 95% CI: 1.07 to 6.39, compared with an aOR of 4.00, 95% CI: 2.53 to 6.30 in unexposed patients. In the subgroup analysis by age, the aOR was 2.81, 95% CI: 1.49 to 5.30 in children, and 4.45, 95% CI: 2.37 to 8.37 in adults. The results were consistent in all sensitivity analyses. Conclusion : This study showed an association between outpatient exposure to systemic corticosteroids with an increased risk of hospitalization for VOE, in both adults and children. Hydroxyurea may reduce this risk in adults. Figure 1 Figure 1. Disclosures Bartolucci: GBT: Consultancy; Emmaus: Consultancy; Fabre Foundation: Research Funding; 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; INNOVHEM: Other: Co-founder; Bluebird: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy; Hemanext: Consultancy; Addmedica: Consultancy, Other: Lecture fees, Research Funding. Moulis: Argenx: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Real World Evidence of Prescription Patterns and Effect of Oxbryta (voxelotor) for Patients with Sickle Cell Disease

Blood ◽

10.1182/blood-2020-143434 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 31-32

Author(s):

Nirmish Shah ◽

Ahmar Urooj Zaidi ◽

Michael U. Callaghan ◽

Darla Liles ◽

Clarissa E. Johnson ◽

...

Keyword(s):

Clinical Trial ◽

Board Of Directors ◽

Sickle Cell ◽

Real World ◽

Research Funding ◽

Cell Disease ◽

Advisory Committees ◽

Real World Evidence ◽

Disease Modifying

Background: Sickle cell disease (SCD) is a chronic illness characterized by anemia, recurrent severe pain and recurrent organ damage, affecting approximately 100,000 persons in the United States. Prior to November 2019, FDA approved SCD disease-modifying treatments included only hydroxyurea (HU) and L-glutamine. However, voxelotor (Oxbryta®) was recently approved under an accelerated approval based on the HOPE study for the treatment of adult and pediatric patients with SCD 12 years of age and older. We aimed to provide real world evidence of the types of patients prescribed voxelotor and preliminary evidence of potential treatment effects. Methods: Patient records were reviewed from five medical centers with comprehensive sickle cell care. All patients prescribed voxelotor from Nov 25, 2019 to July 31, 2020 were included in our analysis. Data reviewed included: patient demographics, hydroxyurea use, as well as pre- and post- voxelotor changes on red cell transfusion number, vaso-occlusive crisis (VOC) and hemoglobin (Hb) values. In addition, voxelotor dosage changes, side effects, and patients perception on impact on their health were recorded. Descriptive and summary statistics were used to provide results. Results: We reviewed data from 60 patients (18 pediatric and 42 adult), across the five centers, who were prescribed voxelotor. Mean age was 33 (SD 13.8) years old with 63% female patients. All patients were African-American/Black and 96% were HbSS (2% Hb SC and 2% HbSOArab). Eighty (80)% were on hydroxyurea, 20% were on chronic transfusions, and 10% were on erythropoietin stimulating agents when prescribed voxelotor. Mean baseline hemoglobin during the 3 months prior to initiation was 7.38 g/dL (SD 1.46) with all patients started at the recommended dose of 1500mg. Annualized VOC events for the year prior to starting voxelotor was 0.62 (SD) or 7.44 VOCs per year. Across all sites, 31 patients were prescribed voxelotor but had either not initiated drug, not returned for follow up labs at time of analysis, or refused to take drug once approved (n=1). Nine patients had only 1 month of follow labs to review and an additional 18 patients with 3 months of follow up labs. These 27 patients were followed for an average of 6.0 months (SD 7.7) on treatment with 4 patients (15%) requiring dose adjustment to 1000mg. Dose adjustments were for side effects including abdominal pain, diarrhea, loose stools and nausea/vomiting. One patient had dosing changed from daily to three times a day. Average hemoglobin during steady state after 1 and 3 months of treatment were 8.6 g/dL (SD 1.8) and 8.0 g/dL (SD 1.8), respectively. In addition, 52% increased by 1g/dL at 1 month (n=21) and 44% increased by 1g/dL at 3 months (n=18). The mean maximum hemoglobin obtained during the 3-month period following initiation of voxelotor was 8.9 (SD 2.1) g/dL. During follow up visits, several patients reported 'more energy' and improvement in 'morning achiness' and 'quality of life', while a few patients noted no change in stamina or well-being. Three patients (5%) had drug discontinued due to becoming pregnant, unexplained elevation of liver enzymes, and due to excessive abdominal pain and nausea. Annualized VOC rates after voxelotor initiation were numerically decreased, although limited by short follow up. Conclusion: We present real world evidence of prescribing patterns and initial outcomes from the use of newly approved voxelotor. We found the majority of patients prescribed voxelotor were the HbSS genotype, on hydroxyurea, and with a mean baseline Hb <7.5 g/dL, indicating an initial focus on more anemic patients. Interestingly, one-fifth of the prescribed patients where on chronic transfusions. Consistent with the HOPE trial, the average Hb levels was found to have increased at 1 month and 3-month follow up. Our preliminary results support an overall increase in hemoglobin in patients treated with voxelotor and we aim to continue following patients over a longer follow up period. This provides important real-world evidence for this newly approved disease-modifying therapy for SCD. Disclosures Shah: Alexion: Speakers Bureau; CSL Behring: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau; Bluebird Bio: Consultancy. Zaidi:Global Blood Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Emmaus Life Sciences: Consultancy, Honoraria; Imara: Consultancy, Honoraria; bluebird bio: Consultancy, Honoraria; Cyclerion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Callaghan:Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Research Funding; Sancillio: Other; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NovoNordisk: Other, Speakers Bureau; Biomarin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Speakers Bureau; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; Alnylum: Current equity holder in publicly-traded company; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Spark: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Hema Biologics: Honoraria, Membership on an entity's Board of Directors or advisory committees. De Castro:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; FORMA Therapeutics: Membership on an entity's Board of Directors or advisory committees; GlycoMimetics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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Prospective Controlled Trial on Endurance Exercise Training in Adult Sickle Cell Disease Patients

Blood ◽

10.1182/blood.v130.suppl_1.991.991 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 991-991

Author(s):

Barnabas Gellen ◽

Laurent Messonnier ◽

Angele Merlet ◽

Etienne Audureau ◽

Thomas Rupp ◽

...

Keyword(s):

Quality Of Life ◽

Sickle Cell Disease ◽

Board Of Directors ◽

Research Funding ◽

Control Group ◽

Cell Disease ◽

Advisory Committees ◽

Endurance Exercise Training ◽

Function Test

Abstract B Gellen and L Messonnier, and L Feasson and P Bartolucci equally contributed to this work Introduction Sickle cell disease (SCD) is the most common inherited disease worldwide. Because favoring the risk of vaso-occlusive crises (VOC), SCD patients are banned from strenuous exercise. We hypothesized that a well-controlled moderate-intensity endurance exercise training (EET) program could improve SCD patients without provoking VOC. Patients and Methods: Weconducted aprospective, multicenter, controlled study with individually tailored Blood lactate-guided (BL) endurance training on a cycloergometer for 8 weeks in adult SCD patients. The primary end point was the submaximal incremental cardio-pulmonary exercise testing (CPET) at a BL concentration of 4 mmol.L-1. Secondary endpoints were: CPET at a BL 2.5 mmol/L and at the first lactic threshold (LT1), BL levels at given workload level (Female: 40W and Male: 60W), safety (pain, VOC and acute chest syndrome), biological and echocardiography parameters, pulmonary function test (PFT), 6-minute walk test (6MWT), quality of life (QoL) and muscle properties and vascularization (biopsy of vastus lateralis muscle). Results: Forty homozygous SCD patients (33±10 years, 23 male) were included. Four patients (3 EET and 1 control) were lost to follow-up. Data of 33 patients (15 EET and 18 controls) were analyzed. EET and control patients were comparable at baseline with regard to CPET, clinical, biological, and resting cardiorespiratory parameters. EET patients presented a significant increase of CPET workload at BL4 (p=0.031), BL2.5 (p=0.003) and LT1 (p<0.0001) compared to the control group that remained unchanged. BL levels at a given level decreased significantly by 18% in the EET group compared to control group (p=0.01). Among the 40 randomized patients, 5 MAE occurred in the control group and 2 in the EET group. Quality of life improved for vitality (p=0.04) and physical activity (p=0.03) in the EET group compared to control group. Thigh biopsy showed in the EET group a significant increase of the proportion of oxidative type I fibers and of COX activity, paralleled by a significant increase in capillary density. No significant alterations were found in the control group. No change was found according to biological and echocardiography parameters, 6MWT and pulmonary function test. Conclusion In SCD patients, EET based on Blood lactate guidance is safe and yields a significant functional benefit. This benefit is linked essentially to improved oxidative function of the peripheral skeletal musculature. Disclosures Galactéros: Addmedica: Membership on an entity's Board of Directors or advisory committees. Bartolucci: GBT: Membership on an entity's Board of Directors or advisory committees; Addmedica: Research Funding; Fondation Fabre: Research Funding; Novartis US: Membership on an entity's Board of Directors or advisory committees.

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Efficacy and Safety of 1500 mg Voxelotor in a Phase 2a Study (GBT440-007) in Adolescents with Sickle Cell Disease

Blood ◽

10.1182/blood-2018-99-117510 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 509-509 ◽

Cited By ~ 1

Author(s):

Clark Brown ◽

Carolyn Hoppe ◽

Adlette Inati ◽

Miguel R. Abboud ◽

Winfred Wang ◽

...

Keyword(s):

Sickle Cell Disease ◽

Adverse Events ◽

Flow Velocity ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Genetic Disorder ◽

Cell Disease ◽

Advisory Committees ◽

Clinical Measures

Abstract Background: Sickle cell disease (SCD) is a genetic disorder caused by a mutated hemoglobin S (HbS) that polymerizes in the deoxygenated state and triggers the downstream effects of red blood cell deformation (sickling), hemolysis, vaso-occlusion, and inflammation. Injury from SCD starts in infancy and accumulates over a lifetime causing end-organ damage and ischemic tissue injury, leading to fatigue, pain (vaso-occlusive crisis), and other clinical complications that are underrecognized, undertreated, and associated with early death. Voxelotor is an oral, once-daily therapy that modulates hemoglobin (Hb) affinity for oxygen, thereby inhibiting Hb polymerization. GBT440-007 is a phase 2a study designed to assess the safety, pharmacokinetics (PK), and efficacy of voxelotor in pediatric patients with SCD (HbSS or HbSβ0 thalassemia). Methods: This ongoing study is evaluating multiple doses of voxelotor at 2 dose levels, 900 mg/day and 1500 mg/day, for 24 weeks in adolescents aged 12 to 17 years. The primary objective is to assess the effect of voxelotor on anemia. Secondary objectives include the effects on clinical measures of hemolysis, PK (PK parameters determined using population PK analysis), cerebral blood flow as assessed by transcranial doppler ultrasound (TCD), and safety. Results: Results for adolescents treated with 900 mg/day have been previously reported. As of June 18, 2018, partial data are available for 13 patients (9 females and 4 males). The median age was 14 years (range, 12-17 years) and median weight was 47 kg (range, 31-72 kg). All participants were on hydroxyurea (HU), and 46% had 2 or more painful crises (range, 2-15) in the year prior to enrollment. The median baseline TCD flow velocity was 112 cm/s (range, 92-177 cm/s), and all were less than 135 cm/s at baseline except for 1 with a baseline of 177 cm/s. Data for measures of hemolysis and TCD are available for 5 adolescents who received voxelotor for 12 weeks. The median increase in Hb was 1.0 g/dL at 12 weeks (Table). Median reductions in reticulocytes and indirect bilirubin were 29% and 18%, respectively (Table), consistent with previously reported results of voxelotor in adults with SCD. Preliminary data suggest linear PK up to 1500 mg, the highest dose evaluated. The adolescent with a baseline conditional TCD (177 cm/s of the bifurcation of the internal carotid artery) on background HU at the maximum tolerated dose (29 mg/kg) had a reduction in TCD flow velocity of 20 cm/s with a concordant increase in Hb of 1.7 g/dL at week 24 with voxelotor compared to baseline and a decrease in reticulocytes from 16.45% to 10.4% (Figure). TCD flow velocities in all other arterial segments showed an overall decline at week 24. All treatment-related adverse events were grade 1 or 2, and there were no treatment-related serious adverse events. Data for all adolescents treated with voxelotor 1500 mg/day for up to 24 weeks will be presented at the conference. Conclusions: Preliminary results indicate that voxelotor at 1500 mg/day was well tolerated. Data from 5 adolescents at 12 weeks show a marked improvement in Hb and reductions in clinical measures of hemolysis. Importantly, hematologic improvements are seen in adolescents already managed at the maximally tolerated dose of HU. Compared to previously reported data at 900 mg/day, this indicates a dose-dependent improvement in hemolytic anemia. One adolescent with conditional TCD, despite background HU, achieved normalized TCD flow velocity after voxelotor therapy. Overall, these results are consistent with in vivo inhibition of HbS polymerization by voxelotor and support the ongoing clinical evaluation of voxelotor as a potential disease-modifying therapy for adolescents with SCD. Disclosures Brown: Global Blood Therapeutics: Consultancy, Research Funding. Inati:Global Blood Therapeutics: Research Funding; Astra Zeneca: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Woods:Global Blood Therapeutics: Research Funding; Pfizer: Research Funding; Guidepoint: Honoraria; Putman: Honoraria; Children's Mercy Hospital: Employment, Membership on an entity's Board of Directors or advisory committees. Hsu:Global Blood Therapeutics: Research Funding; Astra Zeneca: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ironwood: Research Funding; Emmi: Consultancy; Hilton Publishing: Consultancy; Gerson Lehman Group: Consultancy; Guidepoint: Consultancy. Piccone:Novartis: Consultancy. Fong:Global Blood Therapeutics: Employment. Dixon:Global Blood Therapeutics: Employment. Tonda:Global Blood Therapeutics: Employment. Washington:Global Blood Therapeutics: Employment. Lehrer-Graiwer:Global Blood Therapeutics: Employment.

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Diagnostic Imaging Radiation in Severe Sickle Cell Disease: Cancer Risk Implications

Blood ◽

10.1182/blood-2021-149911 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4944-4944

Author(s):

Maria Acevedo-Mendez ◽

Anil Rao ◽

Lewis L. Hsu

Keyword(s):

Sickle Cell Disease ◽

Radiation Exposure ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Ct Scans ◽

Cell Disease ◽

Advisory Committees ◽

Diagnostic Radiation ◽

Cumulative Radiation Exposure

Abstract Introduction: Patients with sickle cell disease (SCD) are repeatedly exposed to diagnostic radiation. Radiographs, computed tomography (CT) and nuclear medicine scans are often ordered for suspected complications caused by sickle cell disease that exposes patients with SCD to ionizing or another form of radiation. A few studies of low-dose cumulative radiation exposure (in people without SCD) suggest that 30 to 100 mSv over 30 decades is associated with higher excess risk of leukemia. New epidemiologic data of low quality suggests that individuals with sickle cell disease (SCD) accumulate "driver mutations" for acute myelogenous leukemia (AML) about 20-30 years earlier than the general population, and have higher risk of AML. In a gene therapy protocol with a few dozen patients, 2 cases of AML have occurred in sickle cell disease and none in thalassemia. It has been reported that children with SCD are frequently exposed to ionizing radiation in the form of plain radiographs, fluoroscopy, computed tomography (CT) scans, bone scans, and other tests. Exposure to ionizing radiation during childhood carries a risk of developing cancer that is directly related to the total radiation dose.Epidemiological data has demonstrated an increase both in diagnostic radiation and in actual or predicted resultant cancer diagnosis. Children are particularly vulnerable to radiation-induced cancer because they are still actively growing and thus are at greater risk of acquiring an oncogenic mutation in an actively dividing cell. Hypothesis: Frequent diagnostic imaging for children and adults with SCD can have significant cumulative radiation exposure that could add excess risk of AML. Methods: The study design was a retrospective chart review. The sample was selected to be enriched for the most severely-affected children and adults in the Sickle Cell Center at UI Health, which provides medical care for over 700 patients with SCD. The subgroup on chronic erythrocytapheresis blood transfusionswere selected as a sample of severe of SCD who are more likely to be exposed to repeated diagnostic radiation. Many have had stroke, which often leads to repeated head CT and cerebral angiograms. Others had pulmonary embolism or acute chest syndrome, which can lead to chest CT angiograms. Other SCD complications with high risk of morbidity or morbidity lead to similar likelihood that patients on chronic exchange transfusion therapy would have histories of multiple imaging studies. Medical records were reviewed for the type and number of all radiographic tests, especially CT scans, during the 10-year period 2011-2020. A second observer confirmed a subset of charts. Standard references were used to estimate radiation exposure in mSv for each type of test. The sum of mSv for each individual was a rough estimate of cumulative radiation in 10 years. The IRB approved the protocol. Results: Chart review on 39 patients (ages 16 - 60y) identified 1,030 radiographic tests with a mean of 26.4 tests/patient. Seven patients had > 50 tests, and one patient had > 100 tests over a 10-year period. Thirty-three patients had at least one CT scan. Eighteen patients had at least 3 CT scans. Twenty patients had cumulative radiation exposure > 30 mSv over a 10-year period, 4 patients had > 100 mSv, and one patient had > 200 mSv. Plain radiographs comprised 71% (736) of the studies and relatively low dose radiation exposure. Discussion: This retrospective study estimated that diagnostic radiography exposed 20 of 39 patients with severe SCD to the range of 30 to 200 mSv over 10 years, mostly from numerous CT scans. This range of cumulative radiation exposure has mixed evidence about possible heightened risk of AML and other cancers. The study is limited by the small sample at a single institution and a heavy bias toward patients with stroke and chest complications, but this severely-affected subgroup comprises many of those eligible for transplant and gene therapy in SCD. Cumulative exposure to diagnostic radiation might be one mechanism for the unexplained patterns of AML in SCD after gene therapy that led to a pause in SCD gene therapy studies for a few months in 2021. Further studies are needed. Disclosures Hsu: Global Blood Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aruvant: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hoffman LaRoche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclerion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Imara: Research Funding; Eli Lilly: Research Funding; Baxalta / Shire / Takeda: Research Funding.

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