scholarly journals Comparison of the Safety Profile of Sickle Cell Disease Patients Treated with Hydroxycarbamide in Off-Label Versus in-Label Prescriptions in the Escort-HU Non Interventional, Prospective, Observational Open-Label Cohort Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2497-2497
Author(s):  
Ersi Voskaridou ◽  
Stephan Lobitz ◽  
Uwe Kordes ◽  
Regine Grosse ◽  
Valentine Brousse ◽  
...  
Keyword(s):  
Immune System ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Safety Profile ◽  
Research Funding ◽  
Therapeutic Indication ◽  
Off Label Use ◽  
Cell Disease ◽  
Off Label ◽  
Label Use

Abstract ESCORT-HU (European Sickle Cell Disease (SCD) COhoRT - HydroxyUrea) is a multicenter prospective non interventional study implemented in Europe, following the European Medical Agency's request to collect more information focused on long-term safety profile of hydroxycarbamide (HU) in SCD patients treated with HU. Primary endpoint of the study is to determine the frequency of adverse events (AEs) under HU treatment Secondary endpoints include the efficacy of HU in labeled indications (prevention of vaso-occlusive complications and of acute thoracic syndrome), frequency of hospitalizations due to SCD events and frequency of blood transfusions. Data collection on the reason for HU initiation permitted to identify in-label (in the therapeutic indication of the European marketing authorization, group 1, G1) and off-label (other therapeutic indication, group 2, G2) prescriptions of HU. Frequency of AEs (including not related to SCD and infections) was compared between adults and children, both in G1 and G2, with focus on the following subclasses: blood and lymphatic system disorders, fever, gastrointestinal disorders, infection, nervous system disorders, skin and subcutaneous tissue disorders and others. As of 6th June 2016 (cut-off date), a cohort of 1047 sickle cell patients have been enrolled in 3 European countries (Greece, 11.4%, Germany, 13.4%, and France, 75.2%). Of the 1047 patients, 845 (80.7%) have an in-label prescription (478 adults and 367 children), 170 (16.2%) an off-label prescription (61 adults and 109 children), and 32 reported unknown or no indication (Table 1a). As usually observed in any disease, the off-label use is more frequent in children compared to adults (p=0.01). Main reasons for off-label prescription were anemia (31%) (n=9 in adults and n=44 in children), abnormal Transcranial Doppler (TCD) values/cerebral vasculopathy (15%) (n=2 in adults and n=24 in children) and sickle cell organopathy including renal impairment (15%) (n=14 in adults and n=12 in children) (Table 1b). These three indications follow recommendations issued by European clinicians and are in accordance with the last version of US guidelines (JAMA 2014). Mean HU daily doses at initiation were respectively 18 mg/kg (G1) and 17.3 mg/kg (G2) in children, and 16.2 mg/kg (G1) and 13.5 mg/kg (G2) in adults. Not SCD-related AEs were respectively reported in 25% and 27.6% of patients in G1 and G2 groups (Table 2a). Focusing on the number of not-SCD related AE reported in each group, 355 AE have been reported in 211 patients in G1 and 73 AE have been reported in 47 patients in G2. Within G1 group, more AEs were reported in adults (30.8%) vs. children (17.4%) (p < 0.01) (Table 2b) but not in G2 group (NS) (Table 2c). When compared by AE type in G1, significant differences appeared between children and adults for the following AE subclasses (p < 0.01): infections more frequent in children as usually observed, renal & urinary disorders, immune system disorders more common in adults. Regarding neoplasms benign, immune system disorders, no malignancy has been reported, but mainly cysts (1 ovary, 2 breast), 1 renal tumor and 1 cutaneous lesion (histological types not provided), 1 other (location not reported) (Table 3). All AEs were more frequent in adults except infections. In conclusion, the current ESCORT-HU data confirm the more frequent off-label use of HU in children, a similar frequency of patients reporting not SCD-related AE between the in-label and off-label groups despite a higher number of AE reported in the in-label group, and a significant difference between children and adults in frequency of AEs in the in-label group. Disclosures De Montalembert: Addmedica: Research Funding; Novartis: Research Funding, Speakers Bureau. Ribeil:Bluebirdbio: Consultancy; Addmedica: Research Funding.

Pharmacological Induction of FOXO3 Is a Potential Treatment for Sickle Cell Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 282-282
Author(s):  
Yankai Zhang ◽  
Jacy R Crosby ◽  
Eric Boerwinkle ◽  
Betty Pace ◽  
Vivien A. Sheehan
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Therapeutic Target ◽  
Off Label Use ◽  
Cell Disease ◽  
Off Label ◽  
Positive Regulator ◽  
Hbf Induction ◽  
Erythroid Maturation ◽  
Label Use

Abstract Sickle cell disease (SCD) affects >100,000 Americans and millions more worldwide. Symptoms and sequelae of SCD can be ameliorated by increasing fetal hemoglobin (HbF, α2γ2) levels. Unfortunately, up to 50% of adult SCD patients treated with hydroxyurea, the only FDA-approved and widely used HbF inducer, do not have a clinically meaningful response to the drug. Additional oral HbF inducing agents, especially those that require less intense laboratory monitoring, are urgently needed. Development of such drugs has been stymied by an incomplete understanding of γ-globin regulation. We hypothesized that natural human genetic variation can be used to identify genes that may be drug targets for HbF induction. To test this hypothesis, we performed whole exome sequencing on 171 pediatric SCD patients to identify variants associated with endogenous HbF levels. Gene-based analysis identified seven unique non-synonymous variations in a Forkhead box O transcription factor, FOXO3, as significantly associated with lower HbF (p=5.6x10-4, β-value of log transformed (ln) HbF= -0.66). Two variants in the α2 subunit of AMPK, a FOXO3 activator, were also associated with reduced HbF (p=1.56x10-4, β-value ln%HbF=-1.5). We then performed functional studies to verify the association between FOXO3 and endogenous HbF levels in an ex vivo model of erythroid differentiation from CD34+ cells isolated from peripheral blood of normal human blood donors. Lentiviral short hairpin RNA (shRNA) knockdown of FOXO3 reduced γ-globin expression from 1 to 0.4, p= 0.0005. While γ-globin expression and protein levels were reduced by FOXO3 knockdown, β-globin levels remained unchanged. These results suggest that FOXO3 is a positive regulator of γ-globin. Morphologic and flow cytometry analysis of primary erythroid culture with and without FOXO3 knockdown indicates that knockdown of FOXO3 delays erythroid maturation, while reducing γ-globin production. We therefore conclude that FOXO3 appears to regulate γ-globin through a specific mechanism rather than through alteration of erythroid maturation kinetics. FOXO3 is a viable therapeutic target for the treatment of individuals with SCD as well as those with quantitative hemoglobinopathies like β-thalassemia, who do not benefit from hydroxyurea due to its delay of erythropoiesis. FOXO3 expression is known to be increased by three drugs, metformin, phenformin, and resveratrol. We found that these drugs also cause FOXO3 to accumulate in the nucleus, where it is active, rather than in the cytoplasm, where FOXO3 is degraded. We have investigated the effects of these agents on FOXO3 and γ-globin expression in K562 cells. Metformin, phenformin and resveratrol increased FOXO3 and γ-globin transcription levels in a dose-dependent manner. We then treated primary erythroid culture cells with a range of metformin doses (20-200µM), with and without a stable dose of 30 µM hydroxyurea. Alone, metformin had a modest effect (1.5 fold) on γ-globin induction at all concentrations. In combination with hydroxyurea, 50 µM metformin increased γ-globin expression 3.7-fold compared to 2.5-fold with hydroxyurea alone when analyzed by RT-qPCR. β-globin levels were unchanged by hydroxyurea or metformin. γ-globin induction persisted through terminal maturation of the culture when measured serially every 5 days. Taken together, our results indicate that not only is FOXO3 is a positive regulator of γ-globin expression, but it is an excellent therapeutic target for HbF induction. Metformin, a well-studied, well tolerated oral agent, will be investigated in combination with hydroxyurea in a phase II trial as an adjunctive agent to increase HbF induction. Disclosures Off Label Use: This presentation will discuss off-label use of metformin as a possible HbF inducing agent..

scholarly journals COVID Symptoms and COVID Anxiety in Sickle Cell Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 16-17
Author(s):  
Wally R Smith ◽  
Benjamin Jaworowski ◽  
Shirley Johnson ◽  
Thokozeni Lipato ◽  
Daniel M Sop
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Research Funding ◽  
Telephone Survey ◽  
Cell Disease ◽  
Weighted Mean ◽  
The Us ◽  
Associated Symptoms ◽  
At Home

Background Even before the US upswing of the current COVID pandemic, the number of sickle cell disease (SCD) patients coming to hospitals and EDs appeared to fall drastically. This happened despite SCD patients having often been heavy utilizers of the ED and hospital for their iconic vaso-occlusive crises (VOC). Though ambulatory SCD clinics quick converted largely to telehealth in order to comply with stay-at-home orders designed to suppress person-to-person transmission, some SCD patients appeared to avoid care, delay care, or refuse doctors' invitations for care. Presumably patients did so out of COVID fears, but this has not been confirmed in the literature. Further, whether these patients had COVID symptoms but stayed at home has not been studied. As part of quality improvement (QI) to conduct COVID surveillance in an adult sickle cell program, we sought to explain and predict SCD health care utilization patterns we were observing, as well as to determine urgent physical and mental health needs of patients who appeared to be avoiding care. Methods Fifteen staff in the Adult Sickle Cell Medical Home at Virginia Commonwealth University, a large urban academic medical center, conducted a telephone survey ("wellness check"was used when we talked to patients) of all known adults with SCD over 19 days in 2020. A staff member confirmed the patient had SCD, asked permission to proceed, then asked about symptoms consistent with COVID-19. At the end of the telephone survey, respondents wer invited to complete an email survey of sickle cell and COVID-19 utilization attitudes (19-33 items, depending on the response pattern, either drawn from the National Health Interview Survey, from the Adult Sickle Cell Quality of Life Measurement quality of care survey, or drafted by the authors), the Sickle Cell Stress Survey-Adult (SCSS-A, a 10-item previously validated survey), and anxiety and depression (PHQ9 of the PRIME-MD). Results Of 622 adults approached by phone call, 353 responded to the following yes/no screening questions regarding the prior 14 days: fever over 100 F 0/353 (0.00%); cough 3/353(0.01%); difficulty breathing 0/353(0.00%); unexplained shortness of breath 2/353(0.01%); sore throat 2/353 (0.01%); unexplained muscle soreness 2/353(0.01%);contact with anyone who tested positive for COVID-19 2/353(0.01%); testing for COVID 19 6/353(0.02%). For QI purposes, we set a threshold of three or more COVID-associated symptoms or the presence of fever as criteria requiring intense telephone or in-person staff monitoring for the following week. Only three patients met criteria. A total of 219/353 had email surveys sent. Of 63 patients (28.8%) who returned email surveys by June 10, 2020, 35.9% had already managed a "pain attack" at home 4 or more times in the prior 12 months, and 45.5% of these said their bad ER experiences were very or somewhat important in that decision. In the prior 14 days, although 30/64 reported a crisis for at least one day, only 4/64 had visited the Emergency Department for pain. On a 0-10 scale, 21/61 patients endorsed "0" for worry that they would be COVID-infected by going for medical care (weighted mean 3.9), but 18/59 endorsed "10" for worry they were more at risk of COVID because of SCD (weighted mean 6.31), and 22/60 endorsed "10" for worry they would fare worse than others if COVID infected (weighted mean 6.97). Many patients forwent "needed" care (16/62) or delayed "needed" care by at least a day (36/61). Eleven patients met criteria for moderately severe to severe depression on the PHQ-9, and 28/63 somewhat or strongly agreed with the statement "death is always on the back of my mind" on the SCSS-A. Conclusions In adolescents and adults with SCD, many were already reticent to come to the ED for pain, but a significant portion reported delays or avoidance of needed care during the early stages of the US COVID pandemic, and few reported using the ED despite over half reporting at least one crisis day in 14. Patients nonetheless reported very few COVID-associated symptoms. Fears of COVID infection/susceptibility may limit visits for needed sickle cell care among adults. Acknowledgements: Mica Ferlis RN, FNP, Caitlin McManus, RN, FNP, Emily Sushko, RN, FNP, Justin West, RN, Kate Osborne, RN, Stefani Vaughan-Sams, Marla Brannon, BS, Nakeiya Williams, BS Disclosures Smith: GlycoMimetics, Inc.: Consultancy; 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.

scholarly journals Clinical and Biomarker Predictors for Avascular Necrosis in Sickle Cell Disease

Blood ◽  
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 &lt; 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.

scholarly journals Alkaline Phosphatase Is Associated with Red Cell Alloimmunization in the Pulmonary Hypertension and Hypoxic Response (PUSH) Sickle Cell Disease Cohort

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-20
Author(s):  
Victoria Brooks ◽  
Oluwalonimi Adebowale ◽  
Victor R. Gordeuk ◽  
Sergei Nekhai ◽  
James G. Taylor
Keyword(s):  
Risk Factors ◽  
Alkaline Phosphatase ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Research Funding ◽  
Severe Disease ◽  
Case Control ◽  
Red Cell ◽  
Cell Disease ◽  
History Of

Background: Blood transfusion is a common therapy for sickle cell disease (SCD). Although, highly effective, a major limitation is development of alloantibodies to minor blood group antigens on donor red cells. Alloimmunization has a prevalence of 2-5% for transfusions in the general population, but it is significantly higher in SCD. Risk factors for alloimmunization have been poorly characterized, although number of lifetime transfusions is an important risk factor. Alloimmunization has been clinically observed in children with a prevalence of about 7%. With development of each antibody, blood donor matching becomes increasingly difficult and expensive with an increased risk for transfusion reactions and diminished availability of compatible red cell units for treatment of SCD. The ability to identify risk factors for developing alloantibodies would be beneficial for clinicians. To identify markers for alloimmunization in SCD, we have analyzed children and adults who developed this complication. Methods: We analyzed The Pulmonary Hypertension and Hypoxic Response in Sickle Cell Disease (PUSH) study, which enrolled n=468 pediatric and n=59 adult SCD subjects. In both children and adults, alloimmunization cases were defined as a history of at least 1 alloantibody. Controls in both cohorts were defined as subjects with no history of alloantibodies and receipt of more than 10 lifetime red cell transfusions. All others within the study who did not meet these criteria were assigned to a third comparison group. To identify differences between cases, controls and all others, we performed univariate analyses (using ANOVA or Kruskal Wallace where appropriate) for clinical parameters and laboratories. Case control comparisons were also performed for selected variables and plasma levels for 11 cytokines. Results were further analyzed using regression modeling. Results: The overall prevalence of alloimmunization was 7.3% among children (34/468 subjects; median age 12, range 3-20 years) compared to 28.8% in adults (17/59 subjects; median age 37, range 18-73 years). When only considering those with &gt;10 lifetime transfusions, the prevalence was considerably higher at 29.3% and 54.8% in children and adults, respectively. At the same time, 8 pediatric (23.5%) and 5 adult (29.4%) alloimmunization cases had received fewer than 10 transfusions. In a 3-way pediatric cohort comparison (cases, controls and all others), risk factors associated with alloimmunization included SS genotype, older age and markers of more severe disease (higher ferritin, WBCs, platelets and total bilirubin). Comparison of cases to controls showed alkaline phosphatase (P=0.05) was significantly lower in cases, whereas AST (P=0.02) was significantly higher even with adjustment for age. Levels of plasma cytokines MCP-1 (P=0.01) and IFNgamma (P=0.08) were lower in cases from a subset of the pediatric cohort. In adults, only 4/59 (6.8%) subjects had never received a lifetime transfusion (all non-SS). In the adult 3-way comparisons, only SS genotype and higher ferritin were associated with alloimmunization. The adult case control analysis showed higher absolute monocyte count (P=0.02), absolute eosinophil count (P=0.04) and absolute basophil count (P=0.008) in association with alloimmunization cases. In addition, alkaline phosphatase was again significantly lower among cases (P=0.02) as seen in the pediatric cohort. There were no significant differences in cytokine levels among adults. Conclusions: When considering only transfused SCD patients, the prevalence of alloimmunization is higher than 30%. As seen in prior studies, higher lifetime red cell transfusions are an important risk factor especially among adults where most patients have received transfusions. Children who develop alloantibodies appear to have laboratory markers of more severe disease, but this is not observed in adults. A novel association observed across both pediatric and adult subjects is a significantly lower serum alkaline phosphatase in those with alloantibodies. The results of this study suggest a need for improved tracking of red cell transfusion therapy in the US for SCD patients due to a high prevalence of alloimmunization. Further study is also needed to elucidate the significance of the alkaline phosphatase association. Disclosures Gordeuk: CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Novartis: Consultancy; Ironwood: Research Funding; Imara: Research Funding.

scholarly journals Cardiac Injury and Microvascular Ischemia in Sickle Cell Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2286-2286
Author(s):  
Kiranveer Kaur ◽  
Ying Huang ◽  
Subha Raman ◽  
Eric H. Kraut ◽  
Payal Desai
Keyword(s):  
Sickle Cell Disease ◽  
Myocardial Perfusion ◽  
Sickle Cell ◽  
Cardiac Mri ◽  
Research Funding ◽  
Cardiac Injury ◽  
Microvascular Disease ◽  
Elevated Troponin ◽  
Cell Disease ◽  
Troponin Elevation

Introduction: Myocardial ischemic injury remains an under recognized problem in patients with sickle cell disease (SCD), for which the exact prevalence remains undefined. SCD patients are known to have microvascular disease, impaired myocardial perfusion reserve and lack of typical epicardial vessel involvement based on prior data. Previous study at our institution has demonstrated that 3/22(13%) patients with clinically stable sickle cell disease had impaired myocardial perfusion reserve but no epicardial coronary artery disease. In this study, we will aim to learn prevalence of cardiac injury and microvascular ischemic disease. We will also evaluate for impact of these findings on overall survival (OS) of SCD patients. Methods: We conducted a retrospective chart review of patients with SCD seen at OSU Wexner Medical Center from July 2005 to July 2015 to identify patients who had elevated troponin-I level or cardiac MRI performed for chest pain. Clinical and laboratory data around the time of cardiac MRI and troponin elevation was collected. Abnormal MRI was defined in three ways: 1) Microvascular disease was defined by presence of subendocardial or myocardial perfusion defects and myocardial scarring. 2) Myocardial disease otherwise includes other findings suggestive but not specific for myocardial ischemia including left ventricular dysfunction, midmyocardial fibrosis, inflammation and regional wall motion abnormalities. 3) Abnormal MRI includes patients described in either 1) or 2). Kaplan-Meier (KM) method was used to evaluate the impact of microvascular disease defined in all 3 ways on OS. Proportional hazards model was fit to estimate the association between troponin elevation and OS, where troponin elevation was treated as a time-dependent variable and OS was measured from time of birth. Results: Sixty-nine (51% male; genotype Hb SS 75%, SC 16%, and Sβ-thal 9%) of 373 SCD patients had either abnormal troponin and/or had cardiac MRI done. Median age was 34 years (range 19-67 years). Of 238 patients who had troponin-I measured over this period, 18 % (n=42) had elevated troponin. 24 of 47 patients with cardiac MRI showed abnormalities described above specific for microvascular disease (n=14, 30%) and myocardial disease otherwise (n=10, 21%). We identified 22 patients with troponin measurement within 30 days before cardiac MRI. Elevated troponin levels predicted MRI abnormalities with sensitivity of 71% (95% confidence interval (CI) 42-92%) and specificity of 63% (95% CI 24-91%). The degree of troponin elevation did not correlate with the MRI abnormality. Hazard ratio of death in patients with elevated troponin was 5.1 (95% CI 2.7-9.6; p<0.0001). While the KM survival curves show lower OS in patients in abnormal MRI (p=0.74) and microvascular disease (p=0.42; Figure 1) group compared with normal MRI, the comparisons were not statistically significant. There was no difference in OS for patients with nonspecific myocardial disease findings (p=0.59). Conclusion: Over a 10-year period, the prevalence of cardiac injury as measured by elevated troponin was 18% (42/238) in patients with atypical chest pain. Among 47 patients who had cardiac MRI performed, 51% were abnormal with 30% having findings specific for microvascular cardiac disease. Troponin elevation appears to significantly increase the risk of all-cause mortality. Patient with microvascular and myocardial ischemic disease tend to have lower OS, but it did not reach statistical significance. This could be one of the potential contributing factors to high early mortality and sudden deaths in SCD patients. Further studies will be needed to elaborate on disease modifying interventions that impact survival in these patients. Disclosures Desai: Novartis: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Potomac: Speakers Bureau; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; University of Pittsburgh: Research Funding; Ironwood: Other: Adjudication Board.

Inflammation, Multiple Blood Transfusions and Osteoclast Activation in Sickle Cell Disease Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1534-1534
Author(s):  
Kevin Cheng ◽  
Mehdi Nouraie ◽  
Xiaomei Niu ◽  
Evadne Moore-King ◽  
Margaret F. Fadojutimi-Akinsi ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Bone Resorption ◽  
Sickle Cell ◽  
Research Funding ◽  
Blood Transfusions ◽  
Serum Concentrations ◽  
Cell Disease ◽  
Howard University ◽  
Tracp 5B ◽  
Multiple Blood

Abstract Abstract 1534 Poster Board I-557 Background Low bone mass density affects more than 65% of adult sickle cell disease patients and correlates with lower hemoglobin and higher ferritin concentrations (1). Increased iron supply promotes osteoclast differentiation and bone resorption (2). Proinflammatory cytokines also promote bone resorption (3). Tartrate resistant acid phosphatase isoform 5b (TRACP-5b) is produced only by activated osteoclasts and therefore serves as a marker of bone resorption (4). Sickle cell disease is a condition of chronic inflammation and patients often suffer from transfusional iron overload as well. In this study we aimed to determine the predictors of bone resorption in patients with sickle cell disease by measuring circulating levels of TRACP-5b. Methods Fifty-nine adult sickle cell disease patients and 22 apparently healthy controls were recruited at Howard University Hospital. Patients were at steady state with no crisis, hospitalization or blood transfusion in the last 3 weeks. Clinical and laboratory information was collected at the time of recruitment and TRACP-5b was measured in non-fasting serum samples using an enzyme immuno assay kit (Quidel, San Diego, CA). Serum concentrations of inflammatory cytokines and growth factors were measured by Multiplex assay (Bio-Rad, Hercules, CA).. Results Sickle cell disease patients had elevated concentrations of TRACP-5b compared to controls (median values of 4.4 vs. 2.4 U/l, P < 0.0001). Among the patients, TRACP-5b concentrations correlated positively with number of blood transfusions (r = 0.19) and serum concentrations of alkaline phosphatase (r=0.46), endothelin-1 (r=0.39), interleukin-8 (r= 0.38), and interleukin-6 (r=0.25). TRACP-5b correlated negatively with RANTES (r = -0.42) and PDGF (r = -0.31). It did not correlate significantly with serum ferritin (r = -0.03), LDH (r = 0.13) or hemoglobin concentration (r = 0.11). Interestingly, TRACP-5b correlated positively with tricuspid regurgitation velocity, which reflects systolic pulmonary artery pressure (r = 0.30). Conclusion Sickle cell patients have elevated steady-state osteoclast activity as reflected in serum TRACP-5b concentrations. Multiple blood transfusions and inflammation are associated findings. Among patients, higher TRACP-5b concentrations are associated with lower concentrations of RANTES and PDGF-BB, factors that influence function of osteoblasts. Further studies are needed to investigate whether common pathways may be involved in osteoclast activation and pulmonary changes in sickle cell disease. Supported by grants number 2 R25 HL003679-08 and 1 R01 HL079912-02 and 1U54HL090508-01 from NHLBI, by Howard University GCRC grant no 2MOI RR10284-10 from NCRR, NIH, Bethesda, MD, and by the intramural research program of the National Institutes of Health. Disclosures Gordeuk: Biomarin: Research Funding; TRF Pharma: Research Funding; Merck: Research Funding; Novartis: Speakers Bureau.

Hydroxyurea Therapy Requires HbF Induction for Clinical Benefit in a Sickle Cell Mouse Model.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 817-817
Author(s):  
Jeffrey D. Lebensburger ◽  
Tamara I Pestina ◽  
Kelli Boyd ◽  
Russell E. Ware ◽  
Derek Persons
Keyword(s):  
Gene Therapy ◽  
Sickle Cell ◽  
Pediatric Patients ◽  
Organ Damage ◽  
Off Label Use ◽  
Cell Disease ◽  
Off Label ◽  
Cell Gene ◽  
Stem Cell Gene ◽  
Hydroxyurea Therapy

Abstract Abstract 817 PURPOSE: To evaluate whether there are clinical benefits from chronic hydroxyurea administration that are independent of HbF induction using a murine SCD model in which fetal hemoglobin (HbF) cannot be induced. METHODS: Cohorts of sex- and aged-matched SCD mice were generated by transplanting lethally irradiated C57/BL6 mice with bone marrow from BERK mice. Only mice fully engrafted with SCD hematopoiesis were used for study. Transplanted SCD mice were injected by intraperitoneal route five days per week. SCD mice with high levels of HbF were generated by stem cell gene transfer using a gamma-globin lentiviral vector followed by transplantation. RESULTS: We identified a dose of hydroxyurea (50 mg/kg) that would lead to a stable, well-tolerated reduction in neutrophil count, much like what is done to titrate dosage in human patients with SCD. Hydroxyurea dosed at 25 mg/kg produced no difference in blood counts compared to control mice, while 75 mg/kg and 100 mg/kg both produced critical pancytopenia. As expected, cellulose acetate gel electrophoresis and HPLC analysis showed that HbF was undetectable in both hydroxyurea-treated and saline-treated mice. Based on this dose-finding data, we treated SCD mice with 50 mg/kg hydroxyurea (n=20) and saline (n=13) five days/week for 20 weeks in order to determine whether chronic hydroxyurea therapy could improve both the anemia and organ damage of SCD. Blood counts obtained after 10 weeks again demonstrated a reduction in white blood cells (26.1 vs. 31.2 ×109/L, p<0.005), absolute neutrophil counts (2.9 vs. 4.6 ×109/L, p<0.005), platelets (780 vs 870 × 109/L, p<0.05), without improvement in the anemia (6.7 vs 6.6 g/dL). Consistent with this data, the serum LDH and total bilirubin values remained elevated, similar to control mice, suggesting no improvement in the rate of hemolysis. Necropsy and pathologic analyses of major organs were performed on six mice from each group after 18-20 weeks of hydroxyurea therapy. Hydroxyurea-treated mice showed no improvement in the severe, multi-organ damage, compared to saline-treated, control mice. In contrast, six SCD mice with high levels of HbF resulting from stem cell gene transfer but not treated with hydroxyurea had a significant correction of their anemia (10.8 g/dL) along with a reduction in both total white blood cell (11.7 ×109/L) and absolute neutrophil counts (2.6 × 109/L). The reduction in the neutrophil count secondary to the correction of the anemia by gene therapy was similar to the levels demonstrated with hydroxyurea administration (hydroxyurea ANC 2.9 × 109/L vs. gene therapy ANC 2.6 × 109/L). Importantly, the SCD mice with high HbF demonstrated no significant organ damage. CONCLUSIONS: Despite causing a significant reduction in the leukocytosis and thrombocytosis, hydroxyurea treatment did not improve the severe anemia and multi-organ disease pathology in SCD mice. In contrast, SCD mice with high levels of HbF resulting from stem cell gene therapy showed resolution of both the anemia and organ pathology. These data suggest that induction of HbF is a necessary and major contributor to the beneficial effects of hydroxyurea in SCD. Disclosures: Off Label Use: Hydroxyurea use in pediatric patients sickle cell disease. This abstract does not discuss the off label use of Hydroxyurea in pediatric patients with sickle cell disease. However, discussion of this abstract would likely result in referencing the off label use of hydroxyurea in pediatric patients with sickle cell disease.

Safety and Efficacy of Sildenafil Therapy for Doppler-Defined Pulmonary Hypertension in Patients with Sickle Cell Disease: Preliminary Results of the Walk-PHaSST Clinical Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 571-571 ◽  
Author(s):  
Roberto F Machado ◽  
Robyn J Barst ◽  
Nancy A Yovetich ◽  
Kathryn L Hassell ◽  
Jonathan C. Goldsmith ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Adverse Events ◽  
Arterial Pressure ◽  
Sickle Cell ◽  
Research Funding ◽  
Cell Disease ◽  
Safety And Efficacy ◽  
Preliminary Results ◽  
Significant Difference

Abstract Abstract 571 Background: Pulmonary hypertension (PH) is associated with increased mortality in patients with sickle cell disease (SCD). Methods: Walk-PHaSST (treatment of Pulmonary Hypertension and Sickle cell disease with Sildenafil Therapy) is a multi-center (10 United States and United Kingdom Centers), placebo-controlled, double-blind 16-week trial evaluating the safety and efficacy of oral sildenafil for the treatment of Doppler-defined PH (tricuspid regurgitant jet velocity [TRV] ≥2.7m/s) in adults and children (aged >12 years) with SCD. The primary endpoint was the six-minute walk distance (6MWD). The study was designed with a planned screening of approximately 1000 subjects, to enroll 132 subjects for inclusion in the nested Main Interventional Trial (MIT). In the screening trial, subjects were evaluated by history and physical examination, laboratory screening, transthoracic Doppler echocardiography and 6MWD. Randomized subjects were stratified by TRV (2.7-2.9 m/s and ≥3.0 m/s), and those in upper strata underwent a right heart catheterization (RHC). Preliminary Results: Of the 722 screened subjects, 150 (26%) had both a TRV ≥2.7 m/s AND 6MWD of 150-500 meters (m), qualifying for MIT enrollment. A total of 74 subjects (13%) were randomized into the MIT. The study was prematurely stopped due to a statistically significant increase in serious adverse events (SAEs) in the sildenafil arm after 33 subjects had completed the 16 week assessments and 74 subjects (37 sildenafil: 23 female, 47 ± 12 years, TRV 3.0 ± 0.4 m/s, 6MWD 378 ± 93 m; 37 placebo: 23 female, 44 ± 14 years, TRV 2.9 ± 0.3 m/s, 6MWD 381 ± 75 m) had been randomized in the MIT. To evaluate safety and efficacy, all 74 subjects were evaluated, with pre-defined primary and secondary endpoint analysis and imputation rules for missing data. Baseline gender, hemoglobin phenotype, TRV and 6MWD were similar between sildenafil and placebo (all p>0.05). There was a significant increase in SAEs in the sildenafil arm (46% vs. 22% of randomized subjects; p=0.048) but no significant difference in adverse events (AEs; 76% vs. 68%; p=0.607). Sickle cell anemia with crisis (hospitalization defining the SAE) accounted for the significant difference in SAEs (35% vs. 11%; p=0.025). In reference to AEs, patients on sildenafil tended to have more headache (27% vs. 14%; p=0.247) and more blurred vision (11% vs. 3%; p=0.358). No other SAEs or AEs by organ system or preferred term were significantly different (all p > 0.43). There were no AEs classified as life-threatening and there was one death in the placebo arm. To assess potential efficacy, all 33 subjects with TRV of ≥3.0 m/s underwent RHC and received a single test dose of 60 mg of sildenafil; data are currently availabel for 22 of those subjects. Although this dose of sildenafil acutely decreased mean pulmonary arterial pressure (p=0.01), and mean systemic arterial pressure (p<0.01), the change in pulmonary vascular resistance was not significant. There were no apparent safety issues with the acute sildenafil dosing (e.g. priapism). After 16 weeks of sildenafil, there was no difference in the change in TRV (adjusted mean change from baseline: sildenafil -0.10 ± 0.08 m/s, placebo -0.13 ± 0.8 m/s; p=0.7) or in 6MWD (adjusted mean change from baseline: sildenafil -17 ± 20.9 m, placebo +1.4 ± 21.8 m; p=0.47). On the Brief Pain Inventory (BPI), sildenafil subjects reported worsening pain during walking (p=0.07; p=0.17) and less enjoyment of life (p=0.09; p=0.04) vs. placebo at the interim visits (6 and 10 week, respectively). For subjects in the sildenafil group, no difference was detected in 6MWD for those experiencing a VOC vs. those without a VOC (adjusted mean 386 ± 15.9 m; 372 ± 11.7 m; p=0.39). Preliminary Conclusions: In conclusion, sildenafil significantly increased rates of VOCs requiring hospitalization vs. placebo. The premature study termination for safety concerns limited the sample size for efficacy assessments; however, further investigation may be warranted in a more select group of patients with optimized hydroxyurea and transfusion therapy. Based on the completed analyses, no relationship has been established between experiencing pain (via serious VOC) and 6MWD. Additional analyses will focus on determining whether pain (as measured by BPI) is correlated with change in 6MWD. Finally, these data suggest a potential role for the cyclic cGMP axis in the pathobiology of VOC and sickle cell disease related pain. Disclosures: Barst: Pfizer: Consultancy, Research Funding. Gibbs:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Girgis:Pfizer: Research Funding. Badesch:Pfizer: Consultancy, Research Funding.

Prevalence of Thrombophilia In Patients with Sickle Cell Disease and Osteonecrosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3184-3184
Author(s):  
Murtadha K. Al-Khabori ◽  
Anil Pathare ◽  
Khalil Al Farsi ◽  
Mohammed Al Huneini ◽  
Salam Alkindi
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Research Funding ◽  
Protein C ◽  
Dna Analysis ◽  
White Cell Count ◽  
Protein S ◽  
Cell Disease ◽  
High Prevalence ◽  
Low Levels

Abstract Abstract 3184 Background: Osteonecrosis (ON) of the femoral and humeral heads is frequently seen in patients with sickle cell disease (SCD). Earlier studies reported a high prevalence of thrombophilia in patients with ON. Aims: To study the prevalence of thrombophilia in patients of SCD with ON. Methods: Case records of SCD patients with ON were retrospectively reviewed for protein S, protein C, and anti-thrombin deficiency, along with activated protein C resistance (APCR). Results: A total of sixty-three patients were identified, 35 of whom were males, with a median age of 21 years (range 15to 46). Median haemoglobin, total white cell count and platelet counts were 10 g/dL (range 7.7to 13.3), 7.5 ×109/L (range 3.4 to 16.7) and 302 ×109/L (range 72 to 1101) respectively. Twenty-eight patients were on hydroxyurea. Thrombophilia testing showed that 29% (95% confidence interval: 17–40), 47% (95% CI: 29–64) and 79% (95% CI: 65–93) of the patients had low levels of functional (<60 unit/dl), total antigenic (<70 unit/dl) and free antigenic (<70 unit/dl) protein S respectively, while 21% (95% CI: 10–31) and 67% (95% CI: 46–87) had low levels of functional (<70 unit/dl) and antigenic (<70 unit/dl) protein C respectively. In addition, 14% (95% CI: 5–23) and 22% (95% CI: 0–56) of the patients had low levels of functional (<80 unit/dl) and antigenic (<80 unit/dl) anti-thrombin levels respectively. Only 2% (95% CI: 0–5) of these patients had an abnormally low APCR (APCR ratio ≤2.3). Summary/Conclusions: Patients with SCD and ON have a high prevalence of thrombophilia. These results indicate that a prospective study with more detailed thrombophilia work-up, along with confirmatory DNA analysis, as well as a study of the role of prophylactic anticoagulation in such patients is highly warranted. Disclosures: Pathare: Sultan Qaboos University: Employment, Research Funding. Alkindi:Sultan Qaboos University: Employment, Research Funding.

A Phase 1 Study of Prasugrel in Subjects with Sickle Cell Disease: Effects on In Vivo Markers of Platelet Activation and of Coagulation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1049-1049
Author(s):  
Joseph A. Jakubowski ◽  
Chunmei Zhou ◽  
David S. Small ◽  
Kenneth J. Winters ◽  
D. Richard Lachno ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Platelet Activation ◽  
Sickle Cell ◽  
Research Funding ◽  
Blood Platelet ◽  
Cell Disease ◽  
Employment Equity ◽  
Equity Ownership ◽  
Adp Receptor

Abstract Abstract 1049 Introduction: Evidence suggests that platelets are activated in sickle cell disease (SCD) and this appears to increase further during painful crises caused by vascular occlusions from sickled red blood cells. Antiplatelet therapy may be useful in reducing the frequency and severity of acute pain episodes and reducing the risk of thrombotic complications. Prasugrel, an ADP receptor antagonist, irreversibly inhibits the P2Y12 ADP receptor, blocking ADP-stimulated platelet activation and aggregation and reducing downstream procoagulant activities. Here we present the first evaluation of prasugrel's effects on markers of in vivo platelet activation and of coagulation in subjects with SCD. Methods: Twenty-six adult subjects were enrolled and 25 completed the study: 12 with SCD and 13 well-matched healthy controls. Subjects were examined before and after 12±2 days of treatment with oral prasugrel (5.0 mg/day for subjects weighing <60 kg and 7.5 mg/day for subjects weighing ≥60 kg). Markers of platelet activation and coagulation included whole-blood platelet-monocyte and -neutrophil aggregates, and whole blood platelet-associated P-selectin and platelet CD40L, all measured by flow cytometry and presented as percent (%) of marker positive cells. Plasma soluble (s) P-selectin, CD40L, and plasma prothrombin fragment 1.2 (F1.2) were evaluated by ELISA. Results: Results from the biomarkers are presented in the table. Prior to prasugrel administration (baseline), subjects with SCD had significantly higher levels of the following biomarkers compared to healthy subjects: Platelet-monocyte aggregates, platelet-neutrophil aggregates, platelet CD40L, and plasma F1.2. In addition, subjects with SCD had numerically higher values of sCD40L, as well as platelet-associated and sP-selectin. Prasugrel treatment resulted in numerical decreases in levels of all biomarkers (with the exception of platelet-associated CD40L for control subjects), most notably in SCD subjects with elevated baseline levels. Prasugrel was safe and well tolerated with no serious adverse events observed during the study. No subject discontinued the study due to an adverse event (AE) and the majority of AEs were mild. No subjects with SCD reported any bleeding-related AEs. Conclusion: In this study, compared to healthy controls, baseline elevation of several platelet-activation and coagulation markers among adult subjects with SCD is consistent with that seen in previous studies of both children and adults with SCD. The decrease in platelet activation biomarkers following 12 days of prasugrel treatment in subjects with SCD suggests prasugrel interrupts SCD-related platelet activation in vivo and raises the possibility that prasugrel may modulate the frequency and/or severity of painful crises associated with SCD. These data support additional studies of the safety and efficacy of prasugrel in the treatment of vascular complications associated with SCD. Disclosures: Jakubowski: Eli Lilly and Company: Employment, Equity Ownership. Off Label Use: This abstract discusses prasugrel treatment in patients with sickle cell disease. Please see USPI for most up-to-date information. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Small:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership. Lachno:Eli Lilly and Company: Employment, Equity Ownership. Frelinger:Takeda: Research Funding; Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Consultancy, Research Funding; GLSynthesis: Research Funding. Howard:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Payne:Eli Lilly and Compnay: Employment, Equity Ownership.

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