Geographic Differences in Phenotype and Treatment of Children with Sickle Cell Anemia from the Multinational DOVE Study

Abstract Background: Sickle cell anemia (SCA) is characterized by significant phenotypic variability. DOVE1 was a Phase 3, double-blind, randomized, parallel-group, placebo-controlled, multinational study that investigated the efficacy and safety of prasugrel, a P2Y12 adenosine diphosphate receptor antagonist, for reduction of vaso-occlusive crises (VOCs), a composite of painful crisis or acute chest syndrome, in 2- to <18-year-olds with SCA (age cohorts: 2 to <6 years, 6 to <12 years, and 12 to <18 years) (NCT01794000). Methods: DOVE was conducted at 51 sites in 13 countries across 4 continents. A total of 341 subjects were randomized (prasugrel, n=171; placebo, n=170) and SCA genotypes (homozygous hemoglobin S; hemoglobin Sβ0 thalassemia) were included. Eligibility required ≥2 VOCs in the prior year. Baseline clinical and laboratory characteristics and study endpoints were compared by region. Since no overall treatment effect was found, data provided reflect the combined 341 subjects (Americas, N=57; sub-Saharan Africa [SSA], N=148; North Africa/Middle East, N=110; Europe, N=26). Results: Per regional enrollment, the largest proportion of subjects were 6 to <12 years in SSA (48.6% [n=72]), 12 to <18 years in the Americas (45.6% [n=26]) and North Africa/Middle East (58.2% [n=64]), but more evenly divided among the 3 age groups in Europe (30.8-34.6% [n=8-9]). Self-reported racial groupings differed by region (p<0.001): 100% white in North Africa/Middle East; 100% black in SSA; 19.2% white, 76.9% black, and 3.8% multiple in Europe; and 1.8% white, 96.4% black, and 1.8% multiple in the Americas. Mean body mass index was <17 in SSA and Europe (15.3 and 16.6 kg/m2) but >18 in North Africa/Middle East and the Americas (18.3 and 18.1 kg/m2) (p<0.001). Mean blood pressures were lowest in SSA (systolic: 99.0 vs. 105.4-108.0 mmHg, p=0.004; diastolic: 58.3 vs. 60.4-62.9 mmHg, p=0.003). The proportion of subjects with history of acute chest syndrome prior to enrollment was lower in SSA (6.1%) than other regions (18.2-66.7%, p<0.001). Mean number of VOCs in the year prior to enrollment was higher in the Americas than other regions (5.8 vs. 3.2-3.4, p=0.041). Hydroxyurea (HU) use at baseline varied by region: 91.2% in the Americas, 72.7% in North Africa/Middle East, 42.3% in Europe, and 6.8% in SSA (p<0.001). For subjects not on HU at baseline (Table 1), mean hemoglobin at baseline was lowest in SSA (7.6 g/dL); reticulocyte count was lowest in the Americas (214.8 billion/L) and highest in Europe (327.8 billion/L) (p=0.004). For all geographic regions, the most frequent serious adverse events (SAEs) were classified as blood and lymphatic system disorders, with the highest percentage reported as painful crisis. The second most frequent SAEs in SSA, North Africa/Middle East, and Europe were various infections and infestations. The second most frequent in the Americas was respiratory, thoracic, and mediastinal disorders; all were reported as acute chest syndrome. The overall rate of VOCs (events per patient-year) was 3.2 in Europe, 3.0 in the Americas, 2.6 in SSA, and 2.0 in North Africa/Middle East. The percentage of patients hospitalized for VOCs was greatest in Europe (76.9%) compared to other regions (28.4-57.9%); however, mean hospital stay per VOC was similar across regions (5.3-6.2 days). The percentage of VOCs causing hospitalization was highest in Europe (67.7%), followed by North Africa/Middle East (48.7%), the Americas (46.5%), and SSA (26.4%). In SSA, the majority of VOCs were managed as outpatient hospital visits (67.9%), whereas other regions more frequently used inpatient hospital visits (33.2-55.2%). Regardless of region, almost all VOCs were treated with analgesics (overall: 99.5%) and approximately half were treated with intravenous (IV) fluids (overall: 54.4%). In contrast, the proportion of VOC-related transfusions was greater in North Africa/Middle East and Europe (18.6% and 18.8%) than in the Americas and SSA (10.0% and 6.4%). Conclusions: In the DOVE study, management of VOCs with analgesics and IV fluids was similar across regions. However, there were regional differences in VOC-related hospitalizations and transfusions that may reflect differences in culture, utilization of resources, disease severity, or a combination of factors. References: 1Heeney MM, et al. A multinational trial of prasugrel for sickle cell vaso-occlusive events. N Engl J Med. 2016;374:625-635. Disclosures Colombatti: Eli Lilly and Company: Research Funding. Heeney:Eli Lilly and Company: Research Funding; Sancilio and Company: Consultancy, Research Funding; Pfizer: Research Funding. Hoppe:Eli Lilly and Company: Consultancy. Ogutu:Eli Lilly and Company: Research Funding. Hassab:Eli Lilly and Company: Research Funding. Zhou:Eli Lilly and Company: Employment, Other: Minor Shareholder. Yao:Eli Lilly and Company: Employment. Brown:Eli Lilly and Company: Employment, Other: Minor Shareholder. Heath:Eli Lilly and Company: Employment. Jakubowski:Eli Lilly and Company: Employment, Other: Minor Shareholder. Abboud:Eli Lilly and Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; MAST Therapeutics: Research Funding; Novartis: Honoraria.

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Predictors of Maternal Morbidity Among Participants Enrolled in the Sickle Cell Disease Implementation Consortium Registry

Blood ◽

10.1182/blood-2020-140743 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 3-3

Author(s):

Rita V Masese ◽

Dominique Bulgin ◽

Liliana Preiss ◽

Mitchell Knisely ◽

Eleanor Stevenson ◽

...

Keyword(s):

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Transfusion Requirement ◽

The United States ◽

Acute Chest Syndrome ◽

Maternal Outcomes ◽

Maternal Complications ◽

Advisory Committees ◽

Increased Risk

Introduction Pregnancy in sickle cell disease (SCD) is associated with an exacerbation of SCD-related complications and an increased risk of maternal complications. The increased risk is partly due to physiologic adaptations in pregnancy, which include increased metabolic demands and a hypercoagulable state. The maternal death rate for SCD is 629 per 100,000 deliveries, compared to 12 per 100,000 deliveries in black women and 6 per 100,000 deliveries in the general population (Raider et al., 2016). Studies on maternal and perinatal outcomes of patients with SCD present inconsistent and conflicting results. Some studies have reported an increase in maternal complications such as pre-eclampsia, acute chest syndrome and thromboembolic events, while other studies have reported no significant risk in adverse maternal outcomes. The inconsistent findings reported in prior studies may be attributed to small sample sizes and single-centered sites. Our study aims to determine the prevalence and predictors of maternal morbidity among participants enrolled in the SCD Implementation Consortium (SCDIC) registry, which is the largest, most geographically diverse SCD participant sample in the United States. Methods This cross-sectional study included women enrolled in the SCDIC registry who had at least one pregnancy event. The SCDIC is composed of eight academic SCD centers across the United States and one data-coordinating center. Participants were enrolled in the SCDIC registry if they were 18 to 45 years of age and had a confirmed diagnosis of SCD. Enrolled participants completed a series of surveys that collected sociodemographic information, SCD and pregnancy history and data abstractions of participants' medical records was completed. Medical complications queried during pregnancy included: vaso-occlusive episodes, acute chest syndrome, blood transfusion requirement, preeclampsia, maternal diabetes and deep venous thrombosis. Descriptive analysis of sociodemographic, clinical and maternal characteristics was conducted. Bivariate analysis was performed using Chi-Square test, Mann-Whitney U test, t-test, and logistic regressions, as appropriate. A p-value of ≤ 0.05 was considered statistically significant for all analysis. Results The study sample included 743 women who had at least one pregnancy event, and a total of 1066 live births. Almost all women (96.3%) were African American, with a median age of 21 years (inter-quartile range of 19 to 23 years) at first birth. The majority had Hb SS SCD genotype (69.5%; 513 of the 738 with SCD genotype data). Of all reported pregnancies, participants did not use hydroxyurea during conception (78%), and pregnancy (84.5%). Only 2.7 % of the women reported using fertility drugs or assisted reproductive procedures. Seventy five percent of the pregnancies that ended in live births had maternal complications. The leading complications were vaso-occlusive episodes (61.2%), pregnancy requiring blood transfusion(s) (33.2%), preeclampsia (15.4%), deep venous thrombosis (5.6%) and acute chest syndrome (7.7%). When the pregnancies were stratified by SCD genotype, women with Hb SS had a higher occurrence of acute chest syndrome (63.4% vs. 26.7%), transfusion requirement (70.8% vs. 21%) and preeclampsia (66.7% vs 22.4%). In the univariate logistic regressions, multiparous women, with a history of adverse maternal outcomes in a previous pregnancy, had higher odds of vaso-occlusive episodes (OR: 3.42; 95% CI: 2.42-4.94) acute chest syndrome (OR:4.99; 95% CI:2.56- 9.48), transfusion requirement (OR:3.86; 95% CI:2.64- 5.69), and pre-eclampsia (OR:3.36; 95% CI:2.05-5.45). Conclusion In this large multicenter registry, we found pregnant women with SCD have significant maternal complications. Early antenatal care by healthcare providers knowledgeable about risk factors for adverse maternal outcomes in SCD is essential improve maternal and fetal outcomes and reduce the maternal death rate for SCD. Disclosures Hankins: Novartis: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; MJH Life Sciences: Consultancy, Patents & Royalties; UptoDate: Consultancy; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; LINKS Incorporate Foundation: Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria. Treadwell:Global Blood Therapeutics: Consultancy; UpToDate: Honoraria. King:Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; RiverVest: Consultancy; Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Kanter: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; BEAM: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; 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; Medscape: Honoraria; Guidepoint Global: Honoraria; bluebird bio, inc: Consultancy, Honoraria; Sanofi: Consultancy. Glassberg:Pfizer: Research Funding; Global Blood Therapeutics: Consultancy; Eli Lilly and Company: Research Funding. Shah:Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; CSL Behring: Consultancy; Bluebird Bio: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau.

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Iron Unloading By Therapeutic Phlebotomy in Previously Transfused Children with Sickle Cell Anemia: The Twitch Experience

Blood ◽

10.1182/blood.v128.22.1018.1018 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1018-1018 ◽

Cited By ~ 1

Author(s):

Banu Aygun ◽

Nicole Mortier ◽

Zora R. Rogers ◽

William Owen ◽

Beng Fuh ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Research Funding ◽

Chelation Therapy ◽

Venous Access ◽

Study Entry ◽

Iron Loading ◽

Advisory Committees

Abstract Background: TCD With Transfusions Changing to Hydroxyurea (TWiTCH, ClinicalTrials.gov NCT01425307), an NHLBI-sponsored Phase III multicenter trial, compared transfusions to hydroxyurea for maintaining TCD velocities in children with sickle cell anemia who previously received transfusions for abnormal TCD velocities. Iron overload was treated with serial phlebotomy in children randomized to hydroxyurea. At the first scheduled interim analysis, non-inferiority of hydroxyurea was demonstrated and the study was terminated prematurely. Methods: Participants randomized to hydroxyurea received decreasing volumes of monthly transfusions during hydroxyurea dose escalation to maximum tolerated dose (MTD), averaging 6-7 months. During this transfusion overlap period, no chelation therapy was given. After hydroxyurea MTD was reached, transfusions were discontinued and children started monthly phlebotomy if their entry liver iron concentration (LIC) by MRI-R2 (FerriScan®) was ≥2 mg Fe/g dry weight liver (DWL). The prescribed phlebotomy volume was 10 mL/kg (maximum 500 mL) with adjustments for anemia (5 mL/kg for Hb 8.0-8.5 g/dL and held if Hb <8.0 g/dL). Phlebotomy was performed over 30 minutes with immediate equal volume normal saline replacement, typically using peripheral venous access. LIC was assessed at study entry, midpoint (12 months), and exit (24 months/early closure). Ferritin was monitored monthly using a centralized laboratory. Iron loading calculations were based on actual transfusion and phlebotomy volumes. Results: Sixty children (mean age 9.7±3.2 years; range 5.2-19.0 years; 48% male) were randomized to the Hydroxyurea Treatment Arm. The average duration of previous transfusions was 4.5±2.8 years. Almost all (51/60, 85%) had previously received chelation, primarily deferasirox, and 48 (80%) were on chelation therapy at study enrollment. Hydroxyurea MTD was achieved in 57 children (95%), and 54 commenced phlebotomy (two had low iron burden with LIC <2 and one had Hb <8.0 g/dL). A total of 914 phlebotomy procedures were scheduled per protocol for these 54 children and 756 (83%) were fully completed. There were 77 procedures cancelled due to anemia and another 81 procedures cancelled due to planned anesthesia (16), provider preference (14), hydroxyurea-related cytopenia (13), intercurrent illness (11), inadequate iv access (9), family request (5) or other (13). In 94% of phlebotomy procedures that were initiated, the full volume was removed; for the remaining 6% (47 procedures), a reduced volume was removed due to loss of venous access (37), symptoms such as headache or lightheadedness (7), or other reasons (3). A total of 18 Adverse Events (17 Grade 2 and one Grade 3) occurred in 14 participants in association with phlebotomy (2.3% prevalence). The most common complication was light headedness/near-syncope (6) followed by anemia (4), hypotension (3), headache (3), and pain at the venous access site (1). One subject had a syncopal episode followed by transient weakness, which was centrally adjudicated as TIA. An average of 53.6±21.8 mL/kg blood was administered in the hydroxyurea-treated arm, which calculates to an average iron loading of 40.1±16.3 mg Fe/kg, while an average of 112 mL/kg of venous blood was removed by phlebotomy, which calculates to an average iron unloading of 36.1±15.7 mg Fe/kg. For the 54 children who received phlebotomy, the average LIC was 12.0± 9.7 mg/g at study entry, 13.4±10.3 at midpoint reflecting overlap transfusions without chelation, and 9.7±8.9 at study exit reflecting serial phlebotomy, for an average net LIC decrease of 2.3±4.1 mg/g. Average serum ferritin at study entry was 3105±741 ng/mL and 1392±1542 ng/mL at study exit. For 39 children who completed all 24 months of treatment before study closure, the overall average LIC decrease was 3.2±3.8 mg/gram DWL and 10 had final LIC measurements <3 mg Fe/g. Calculated net iron loading was not significantly associated with measured changes in LIC or ferritin. Conclusions: In the TWiTCH trial, phlebotomy was a feasible, safe, well-tolerated, and effective treatment for transfusional iron overload in children with sickle cell anemia. Although initial overlap transfusions without chelation limited the phlebotomy effects, in children who reached hydroxyurea MTD and discontinued chronic transfusions, monthly phlebotomy led to net iron unloading and lower LIC, and significantly reduced iron burden. Disclosures Rogers: Apopharma: Consultancy. Kalfa:Baxter/Baxalta/Shire: Research Funding. Kwiatkowski:Sideris Pharmaceuticals: Consultancy; Luitpold Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Apopharma: Research Funding; Ionis pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Shire Pharmaceuticals: Consultancy. Wood:World Care Clinical: Consultancy; Biomed Informatics: Consultancy; Biomed Informatics: Consultancy; Celgene: Consultancy; Celgene: Consultancy; AMAG: Consultancy; Apopharma: Consultancy; Apopharma: Consultancy; AMAG: Consultancy; World Care Clinical: Consultancy; Vifor: Consultancy; Vifor: Consultancy; Ionis Pharmaceuticals: Consultancy; Ionis Pharmaceuticals: Consultancy. Ware:Global Blood Therapeutics: Consultancy; Biomedomics: Research Funding; Bayer Pharmaceuticals: Consultancy; Addmedica: Research Funding; Nova Laboratories: Consultancy; Bristol Myers Squibb: Research Funding.

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Outcomes in Children with Severe Vasculopathy from Sickle Cell Anemia after Treatment with Chronic Transfusion, Surgical Revascularization and/or Allogenic Hematopoetic Stem Cell Transplantation

Blood ◽

10.1182/blood-2018-99-118693 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1098-1098

Author(s):

Courtney W. Johnson ◽

Suvankar Majumdar ◽

Andrew D. Campbell ◽

Suresh Magge ◽

Deepika S. Darbari ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Research Funding ◽

Moyamoya Syndrome ◽

Surgical Revascularization ◽

Advisory Committees ◽

Time Of Intervention

Abstract Background: Cerebral vasculopathy is a frequent complication of sickle cell anemia (SCA) and is associated with a high risk for stroke. This vasculopathy seen in SCA can be progressive and severe. Sickle cell patients with severe vasculopathy, including Moyamoya syndrome are at increased risk for neurological disabilities and death. While chronic transfusions decrease the risk of stroke in SCA; unfortunately, progression of vasculopathy can occur despite treatment. Limited data exists regarding long term outcomes for this population. We evaluated effectiveness of three treatment approaches at our center, namely chronic transfusions, surgical revascularization plus chronic transfusions and allogenic hematopoietic stem cell transplant (HSCT). Methods: A retrospective chart review was preformed to identify patients with SCA (hemoglobin SS, Sβ0) and severe vasculopathy including Moyamoya syndrome between 1986 to 2017. Severe vasculopathy was defined as having at least one cerebral artery with > 70% stenosis and/or occlusion as seen on MR angiogram (MRA), CT angiogram (CTA) or conventional angiogram (DSA) as determined by a neuroradiologist at our institution. Patients were identified from an institutional stroke database. Patients were included for analysis if they received at least one of the following: chronic transfusions, surgical revascularization (i.e. encephalo-duro-arterio-synagiosis (EDAS) plus chronic transfusions or HSCT. For HSCT, all graft types (bone marrow, peripheral blood stem cells, umbilical cord blood), conditioning regimens and donor types (related, unrelated and haploidentical) were included. Time to event analyses were performed from the time of intervention (transfusion, HSCT, EDAS/chronic transfusions) using overt clinical stroke, new silent infarcts, progression of vasculopathy or new vasculopathy. Survival curves were analyzed using the log-rank (Mantel-Cox) test. Results: Of 35 patients identified, 54% (n =19) underwent chronic transfusions, 23% (n=8) of patients underwent HSCT after being on chronic transfusions, 23% (n=8) underwent EDAS with chronic transfusions and 1 patient underwent each of the above three modalities (Table 1). Median age at time of intervention was similar for all three cohorts (Table 1). Males were overrepresented in all treatment arms (62.5-79% of patients). Average hemoglobin level prior to intervention was also similar: 7.6 g/dL (IQR 7.1-8.3) for the chronic transfusion cohort, 7.3 gm/dL (IQR 6.3-8.2) for the HSCT cohort, and 7.5 gm/dL (IQR 7.2-8) for the EDAS/chronic transfusion cohort. Absolute reticulocyte count was 492.9 K/ul (IQR 358.4-550) for the chronic transfusion group, 389.4 (IQR 174.3-449) for HSCT, and 250.2 (IQR 107.3-393) for EDAS/chronic transfusions (p=0.08). One patient died of overt stroke in the chronic transfusion cohort. The median follow-up times for the transfusion, HSCT and EDAS plus transfusion groups were 4.4, 2.4 and 6 years respectively. Time from date of intervention (transfusion, HSCT, EDAS) to overt clinical or silent stroke was evaluated (Fig 1). Two of the nineteen patients in the chronic transfusion cohort suffered an overt stroke, while one of eight and two of eight had strokes in the post-HSCT and EDAS plus chronic transfusion cohorts respectively. Fourteen of nineteen (74%) in the chronic transfusion cohort had progression of severe vasculopathy after being on transfusions while two of eight (25%) in the HSCT and four of the eight (50%) patients in the EDAS plus chronic transfusion cohorts had progression. The one patient with all three different interventions did not have additional infarction (clinical or silent) or vasculopathy progression during 1.5 years of follow-up. Conclusions: The risk for cerebral infarction and/or vasculopathy progression after initiation of treatment with either chronic transfusion, HSCT or EDAS is still a major concern. Our data suggest HSCT and surgical revascularization with chronic transfusion provide the greatest benefit in reducing stroke risk and HSCT reduces risk for progression of a severe vasculopathy. Additional, large population studies are needed to clarify the risk. Disclosures Majumdar: NIMHD: Research Funding. Campbell:Functional Fluitics: 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, Research Funding.

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An Analysis Of The Pediatric Sub-Group From The Phase 2 Study Of GMI 1070 – A Novel Agent For The Vaso-Occlusive Crisis Of Sickle Cell Anemia

Blood ◽

10.1182/blood.v122.21.2206.2206 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2206-2206

Author(s):

Timothy L. McCavit ◽

Lakshmanan Krishnamurti ◽

Lewis L. Hsu ◽

Charles T. Quinn ◽

Isaac Odame ◽

...

Keyword(s):

Median Time ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Research Funding ◽

Study Drug ◽

Acute Chest Syndrome ◽

Phase 2 ◽

Opioid Use ◽

Advisory Committees ◽

Secondary Outcomes

Abstract Introduction Vaso-occlusive crisis (VOC) is the hallmark of sickle cell anemia (SCA), yet VOC treatment has not improved in decades. Recently the role of adhesive interactions between leukocytes, erythrocytes, and the vascular endothelium has been recognized in VOC. GMI 1070, a pan-selectin inhibitor, was designed to decrease the contribution of leukocyte adhesion to VOC. Herein, we report a sub-analysis of the pediatric patients enrolled in a study of GMI 1070 with the aims of determining the efficacy and toxicities in this subgroup and comparing pediatric to adult patients. Methods This multi-center, randomized, double-blind, placebo-controlled phase 2 trial enrolled afebrile patients ≥ 12 yrs with HbSS or HbSβ0 thalassemia presenting with VOC. Subjects had no organ dysfunction or other acute SCA complications. GMI 1070 was administered IV as a loading dose, then in up to 14 q12 h maintenance doses. Following a pre-specified interim PK analysis including 1 pediatric and 10 adult subjects, the loading and maintenance doses were doubled. Other management was at the discretion of the treating physician. Pain intensity was measured with a 10 cm visual analog scale. The primary outcome was time to resolution of VOC, defined as either a sustained 1.5 cm decrease in the pain score and cessation of IV analgesics; readiness for discharge; or hospital discharge. Secondary outcomes included time to discharge, time to transition from IV to oral analgesics, opioid usage, and safety profile. Median time-to-event was compared between arms using the Kaplan-Meier (KM) method. Analysis of covariance was used to compare the mean hourly opioid use, by hospital day. Results Seven sites enrolled 20 pediatric subjects: GMI 1070 - 13 vs placebo - 7. The median age was 14 years, and 40% were female. Time to 1st dose of study drug was a mean of 15 h from initial medical evaluation. Median length of stay was 105 h. The GMI 1070 arm had a 60.7 h reduction in the median time to resolution of VOC compared to placebo (Fig. 1a). Similarly, the median difference in time to transition to oral opioids and time to discharge were clinically significant between GMI 1070 and placebo at 87.8 h and 96 h, respectively (Fig. 1b & 1c). Mean hourly opioid use was lower with GMI 1070 than placebo in the first 24 h, but the trajectory thereafter did not differ (Fig. 1d). The effect of GMI 1070 on the primary and secondary outcomes was similar for pediatric and adult subjects (Table 1). Differences between pediatric and adult subjects included which opioid was used (pediatrics – 80% morphine vs adults – 80% hydromorphone). Also more pediatric subjects received IV antibiotics (Table 1), particularly in the first 24 hrs of study drug (pediatrics – 35% vs adults – 14%). The proportion of pediatric subjects experiencing a serious adverse event (SAE) was similar between arms (GMI 1070 – 31% vs placebo – 43%). Most SAE's were VOC recurrence; 1 SAE was an episode of acute chest syndrome (ACS) in the GMI 1070 arm (0 in the placebo arm). Of 4 total ACS events (1 SAE, 3 AE), 3 occurred within 24 h of 1st study drug, 1 required red blood cell transfusion and 0 required intensive care. No severe or unusual infections occurred in either arm. Conclusions GMI 1070 is a promising agent for reducing duration of VOC in SCA. Compared to adults, pediatric subjects demonstrated similar efficacy and safety. The ACS cases in the GMI 1070 arm are noteworthy but are not definitively associated with study drug. The strong efficacy signal in adolescents, along with minimal safety concerns, warrants inclusion of younger children in a subsequent phase 3 clinical trial of GMI 1070. Disclosures: McCavit: Pfizer, Inc.: Consultancy; GlycoMimetics, Inc.: Research Funding. Krishnamurti:GlycoMimetics, Inc.: Research Funding. Hsu:GlycoMimetics, Inc.: Research Funding. Quinn:Glycomimetics: Research Funding; Eli Lilly: Research Funding; MAST Therapeutics: Research Funding; American Society of Hematology: Advisory Committees, Advisory Committees Other, Honoraria. Odame:Glycomimetics: Research Funding. Alvarez:Glycomimetics: Research Funding. Driscoll:Glycomimetics: Research Funding. Smith-Whitley:GlycoMimetics, Inc: Research Funding. Rhee:Rho, Inc.: Employment; GlycoMimetics, Inc.: Research Funding. Wun:Emmaus, Inc.: Clinical Adjudication Committee Other; Pfizer, Inc.: Consultancy; GlycoMimetics: Research Funding. Telen:GlycoMimetics, Inc.: Research Funding; Dilaforette, NA: Research Funding; Pfizer, Inc.: Consultancy. Thackray:GlycoMimetics, Inc.: Employment, Equity Ownership.

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A Pilot Study of Eptifibatide for Treatment of Acute Pain Episodes in Sickle Cell Disease.

Blood ◽

10.1182/blood.v120.21.2102.2102 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2102-2102

Author(s):

Payal C Desai ◽

Julia Brittain ◽

Susan Jones ◽

Adam McDonald ◽

Douglas R Wilson ◽

...

Keyword(s):

Sickle Cell Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Acute Pain ◽

Research Funding ◽

Point Estimate ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Opioid Use ◽

Advisory Committees

Abstract Abstract 2102 Background: Despite the abundant laboratory evidence of platelet activation and inflammation in sickle cell disease (SCD), the contribution of these changes to the pathogenesis of SCD remains uncertain. Patients with SCD exhibit increased platelet activation in the non-crisis, “steady state,” and further increases with acute pain episodes. In addition, levels of the inflammatory mediator, CD40 ligand (CD40L) are increased in the plasma and significantly reduced in the platelets of SCD patients compared to healthy individuals. CD40L may contribute to the pathogenesis of acute pain episodes. Despite an improved understanding of the pathophysiology of SCD, the treatment of acute pain episodes is supportive. We performed a randomized, placebo-controlled study to evaluate the safety and efficacy of eptifibatide, a synthetic peptide inhibitor of the glycoprotein (GP) IIb/IIIa receptor, in patients with SCD during acute painful episodes. Methods: In this single site placebo-controlled trial, eligible patients admitted for acute painful episodes received eptifibatide (two 180 mg/kg boluses 10 minutes apart, followed by a continuous infusion at 2 mg/kg/min for 6 hours) or placebo at a ratio of 2:1. The Post-Treatment Phase lasted for up to 7 days or until resolution of the crisis, whichever was shorter, but no less than 24 hours after discontinuation of infusion. The Follow-up Phase included safety evaluations obtained 14 to 17 days and 28 to 35 days after discontinuation of infusion. The primary outcomes were major bleeding episodes and the largest observed decrease in platelet count during the study. We also evaluated the effect of eptifibatide on the duration of acute pain episodes, pain intensity, duration of hospitalization, total opioid use and acute chest syndrome. Results: Thirteen patients (SS - 10, Sb0 - 2, SC - 1) were randomized to receive either eptifibatide (N=9; 6 females; median age - 25 years) or placebo (N=4; 3 females; median age - 31 years). One patient in the eptifibatide arm withdrew consent following completion of study drug infusion and 1 patient in the placebo arm was withdrawn early because she did not meet eligibility criteria. In the intent-to-treat analysis, there were no major bleeding episodes in either group (point estimate of difference in eptifibatide vs. placebo proportion: 0.0, 95% CI; −0.60, 0.37).There was one minor bleeding episode in a patient on the eptifibatide arm (point estimate of difference in eptifibatide vs. placebo proportion: 0.11, 95% CI: −0.502, 0.494). There was a trend for the largest decrease in platelet count to be greater in the eptifibatide arm compared to the placebo arm, although the difference was not statistically significant (Hodges-Lehman estimate of location shift for eptifibatide vs. placebo: −82, 95% CI; −281, 54). There was no significant difference in the proportion of patients with thrombocytopenia between the treatment groups (point estimate of difference in eptifibatide vs. placebo proportion: 0.11, 95% CI: −0.587, 0.495). The median time to discharge and the median time to crisis resolution were 3.0 days for both treatment arms. The median total opioid use was 400.2 morphine equivalents (ME) for the eptifibatide group and 1471 ME for the placebo group (Hodges-Lehman estimate of location shift for eptifibatide vs. placebo: −65.8, 95% CI: −2519, 1700). There was one episode of acute chest syndrome in each treatment arm. Conclusions: In this small study of SCD patients hospitalized with acute painful episodes, eptifibatide appeared to be safe, but did not improve the times to crisis resolution or hospital discharge. Eptifibatide was associated with a reduced requirement for opioid analgesics, although the difference was not statistically significant. Clinicaltrials.gov Identifier: NCT00834899. Disclosures: Parise: BD: Consultancy; Biogen-Idec: Consultancy; NIH: Research Funding; AHA: Research Funding; SCDAC-NIH: Membership on an entity's Board of Directors or advisory committees; BRI Milwaukee: Membership on an entity's Board of Directors or advisory committees. Ataga:Pfizer: Consultancy; HemaQuest Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adventrx Pharmaceuticals: Consultancy. Off Label Use: Eptifibatide, a glycoprotein IIb/IIIa inhibitor, was evaluated as treatment for acute pain episodes in patients with sickle cell disease.

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Opioid Analgesics Are Associated with Albuminuria in Adult Patients with Sickle Cell Anemia

Blood ◽

10.1182/blood-2019-131368 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2308-2308

Author(s):

Ashley Thrower ◽

Zhou Laura ◽

Vimal K. Derebail ◽

David Wichlan ◽

Ashley Smith ◽

...

Keyword(s):

Board Of Directors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Research Funding ◽

Total Bilirubin ◽

Opioid Analgesics ◽

Cell Disease ◽

Opioid Use ◽

Advisory Committees ◽

Morphine Equivalent

Introduction: Sickle cell disease (SCD) is characterized by hemolytic anemia and vaso-occlusive episodes associated with multi-organ dysfunction. Chronic kidney disease is a common complication and associated with increased mortality. Opioid analgesics are used in SCD patients for pain relief, often starting at a young age and continuing through adulthood. In SCD mouse models, chronic opioid exposure worsens nephropathy leading to increased glomerular mesangial volume and fractional kidney mass as well as albuminuria. We evaluated the association of opioid analgesic use and albuminuria in adult patients with sickle cell disease. Methods: We conducted a cross-sectional study of patients with sickle cell anemia (HbSS and HbSβ0thalassemia) recruited into a prospective natural history cohort at two adult Sickle Cell Centers. Patients were enrolled during routine clinic visits and in a non-crisis, "steady state". We excluded patients with bone marrow or kidney transplant, diabetic nephropathy, hepatitis B or C, HIV, lupus or other glomerular diseases and those on dialysis. We collected data on treatment including use of hydroxyurea and ACE-inhibitors or angiotensin receptor blockers (ACE-I/ARB). Opioid exposure was determined from state narcotic databases for each patient during the year preceding enrollment. Clinical laboratory tests, including spot urine albumin-creatinine ratio (UACR), were acquired at the baseline visit. Patients were considered to have albuminuria if UACR was ≥30mg/g creatinine. Total opioid use, converted to morphine-equivalent units, was quantified in the preceding 1 month, 6 months, and 12 months. Morphine exposure in each time interval was categorized into three groups for analysis: no morphine exposure, exposure ≤50thpercentile, and exposure >50thpercentile. We used multivariable logistic regression models to assess the relationship between opioid use categories and presence of albuminuria adjusting for the following covariates: age, sex, hydroxyurea use, ACE-I/ARB use, total bilirubin, direct bilirubin, hemoglobin, white blood cell (WBC) count, systolic and diastolic blood pressure, hemoglobin F%, estimated glomerular filtration rate (eGFR) and site of enrollment. Results: Seventy-eight patients with sickle cell anemia who had complete data for the variables of interest and outcome were included. Mean age was 33.1 years (SD 11.5) and 45 (57.7 %) were female. When comparing patients by albuminuria status (Table), patients with albuminuria were older (36.1 v 30.8 years) and less likely to be female (45.5 % v 66.7 %). Patients with albuminuria had both higher systolic and diastolic blood pressures. Hydroxyurea use was similar between both groups, but albuminuria patients were more likely to receive ACE-I/ARB therapy. Patients with albuminuria were more likely to have lower hemoglobin, higher total bilirubin, alkaline phosphatase and absolute reticulocyte count. Patients with albuminuria also had lower eGFR and greater opioid exposure over each of the three time intervals evaluated. Opioid use in the preceding 1 month was not associated with albuminuria in the adjusted model (p=0.6). Opioid use in the preceding 6 months was associated with albuminuria (p=0.02), patients with opioid exposure >50thpercentile (>5500 mg of morphine equivalent) having a 39.1 (95% CI: 2.1, 719.8; p=0.01) higher odds of developing albuminuria compared to those without opioid exposure. Patients with less than the 50thpercentile also trended towards a higher odds of albuminuria (OR 6.3, 95% CI: 0.7, 58.1; p=0.1), but did not reach statistical significance. As estimates for odds of albuminuria were similar for patients with > 50thpercentile and ≤50thpercentile of opioid exposure over twelve months of exposure, we collapsed the categories into "no opioid exposure" vs. "any opioid exposure." Patients with any amount of opioid use over the preceding 12 months had a higher odds of albuminuria (OR 11.0, 95% CI 1.2, 104.4; p=0.04). Conclusion: While limited in sample size, our data demonstrate that higher opioid exposure over the preceding 6 months and any opioid exposure in the preceding year were independently associated with albuminuria in patients with sickle cell anemia. These findings suggest that opioid exposure may be associated with kidney disease in patients with SCD. This association warrants additional study given the common use of these agents in SCD. Disclosures Derebail: Retrophin: Consultancy; RTI: Honoraria; Novartis: Consultancy. Ataga:Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Emmaus Life Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Modus Therapeutics: Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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The Oxygenscan: A Rapid and Reproducible Test to Determine Patient-Specific, Clinically Relevant Biomarkers of Disease Severity in Sickle Cell Anemia

Blood ◽

10.1182/blood-2018-99-112930 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2360-2360

Author(s):

Minke A.E, Rab ◽

Celeste K Kanne ◽

Brigitte A. van Oirschot ◽

Jennifer F. Bos ◽

Maite Elizabeth Houwing ◽

...

Keyword(s):

Board Of Directors ◽

Disease Severity ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Research Funding ◽

Patient Specific ◽

Advisory Committees ◽

Laboratory Parameters ◽

Oxygen Concentrations ◽

Rbc Deformability

Abstract Background: In sickle cell anemia (SCA), hemoglobin S (HbS) polymerizes upon deoxygenation, resulting in sickling of red blood cells (RBCs). These deoxygenated RBCs have strongly reduced deformability, which contributes to the etiology of vaso-occlusive crises and chronic hemolytic anemia. There are no widely available clinical laboratory tests to directly monitor effects of disease modifying therapies (i.e. hydroxyurea) on RBC deformability. RBC deformability can be measured using a Laser Optical Rotational Red Cell Analyzer (Lorrca) ektacytometer (RR Mechatronics, the Netherlands), which measures RBC deformability over a range of osmolalities. Recently, a new module was added which consists of a method to measure RBC deformability, expressed as Elongation Index (EI), during controlled deoxygenation. This test, termed oxygenscan, has 3 key read out parameters: 1) EImax, which represents RBC deformability at normoxia; 2) EImin represents deformability upon deoxygenation; and 3) the point of sickling (PoS), the point at which a >5% decrease in EI is observed during deoxygenation, reflecting the patient-specific pO2 at which sickling begins (Figure 1). In this study, we correlated laboratory parameters associated with SCA disease severity with oxygenscan parameters to establish the clinical utility of this test. Methods: The discovery cohort consisted of 15 SCA patients (median age 22.0 years, 33.3% on hydroxyurea (HU)) enrolled at University Medical Center Utrecht (UMCU). The validation cohort consisted of 21 patients with SCA (median age 12.5 years, 76.2% on HU) from Texas Children's Hematology Center (TCHC). Oxygenscans were carried out in duplicates at both sites. Percentage dense RBC (%DRBC) were measured using an ADVIA hematology analyzer (Siemens) at TCHC only. In this study, we used Pearson's correlation to test for linear correlations between oxygenscan parameters EImax, EImin and PoS and clinically relevant laboratory parameters: total hemoglobin (Hb), absolute reticulocyte count (ARC), %HbS and %HbF, and %DRBC. Results: In both cohorts PoS significantly positively correlated with ARC (Figure 2A-B). In the UMCU cohort, total Hb levels also significantly positively correlated with EImax (Figure 2C), which was validated in the TCHC cohort (Figure 2D). HbF positively correlated with the EImin in both cohorts (Figure 2E-F). EImin also significantly negatively correlated with HbS (r=-0.828 p=<0.001 in the UMCU cohort, r=-0.936, p=<0.001 in the TCHC cohort data not shown). EImax showed a strong negative correlation with the %DRBC (Figure 2G) in the TCHC cohort. Individual test results were highly reproducible at both sites, with a median coefficient of variability of all tested parameters below 3%. Conclusion: The oxygenscan is a semi-automated, inexpensive, highly reproducible, and rapid test to fully characterize patient-specific RBC deformability under a range of oxygen concentrations. Key oxygenscan measurements- PoS, EImin, and EImax- correlated with known measures of SCA disease severity, namely ARC, HbF, HbS, total Hb and %DRBC. Patients with higher reticulocyte counts showed a clinically unfavorable increase of oxygen concentration at which RBCs start to sickle (termed PoS), than patients with lower ARC. Patients with higher HbF had more deformable RBCs even at the lowest oxygen concentrations, or EImin, while patients with higher HbS had lower EImin (low values indicate poor deformability under deoxygenated conditions). Patients with high %DRBC had lower EImax, indicating poor RBC deformability at normoxic conditions. Conversely, patients with high total Hb had high EImax. The very strong correlations of key oxygenscan measurements with different measures of SCA disease severity suggest that these parameters could be exploited as useful biomarkers of clinical severity and in the follow-up and treatment of SCA patients and warrant further investigation. Disclosures Rab: RR Mechatronics: Research Funding. Bos:RR Mechatronics: Research Funding. Cnossen:Roche: Research Funding; CSL Behring: Research Funding; Novartis: Research Funding; Novo Nordisk: Research Funding; Bayer: Research Funding; Shire: Research Funding; Pfizer: Research Funding. Schutgens:Bayer: Research Funding; CSL Behring: Research Funding; Pfizer: Research Funding; Uniqure BV: Research Funding; Novo Nordisk: Research Funding; Baxalta/Shire: Research Funding. van Wijk:Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; RR Mechatronics: Research Funding. van Beers:RR Mechatronics: Research Funding; Bayer: Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Results from the Displace Consortium: Practice Patterns on the Use of Transcranial Doppler Screening for Risk of Stroke in Children with Sickle Cell Anemia

Blood ◽

10.1182/blood-2018-99-116709 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4697-4697

Author(s):

Shannon Phillips ◽

Martina Mueller ◽

Alyssa M Schlenz ◽

Cathy Melvin ◽

Robert J. Adams ◽

...

Keyword(s):

Board Of Directors ◽

Sickle Cell ◽

Cerebral Artery ◽

Sickle Cell Anemia ◽

Transcranial Doppler ◽

Research Funding ◽

Practice Patterns ◽

The United States ◽

Care Providers ◽

Advisory Committees

Abstract Introduction: Stroke is one of the most devastating complications of sickle cell anemia (SCA). The STOP (Stroke Prevention Trial in Sickle Cell Anemia) protocol has been adopted by National Heart Lung and Blood Institute (NHLBI) as the guideline for stroke screening using transcranial Doppler ultrasound (TCD) and prevention with chronic red cell transfusion therapy (CRCT). Evidence from the STOP I/II studies indicates the protocol is highly effective, yet wide scale implementation has not been achieved. The DISPLACE (Dissemination and Implementation Looking at the Care Environment) project is a multicenter, NHLBI funded consortium of 28 sites across the United States whose purpose is to identify barriers to the implementation of the STOP protocol and test novel methods for overcoming barriers. The purpose of this study was to use data on practice patterns to evaluate current measurement and practice standards at DISPLACE consortia sites. This abstract presents reported TCD screening and CRCT practices. Methods: A practice patterns survey was sent to the principal investigator (PI) for each DISPLACE site via RedCap ©. PIs were hematology/oncology specialty care providers for children with SCA. Sites represent urban and rural regions, large and small academic institutions, and community-based institutions. The survey was developed by the study investigators; questions were predominantly in a multiple-choice format. Items pertaining to TCD screening included: screening technique (including type of TCD); screening frequency; follow-up for abnormal, conditional, and inadequate results; standard value ranges. Results: All 28 PIs completed the survey. About half of the respondents were female (53.5%). Most identified as White (77.8%), followed by Asian (11.1%) and Black or African American (7.4%). Two identified as Hispanic or Latino (7.4%). Slightly more sites reported using standard TCD (57.1%) versus imaging TCD (TCDi) (42.9%). To calculate the time-averaged mean of the maximum (TAMM) velocities and characterize TCD results, nearly all sites use the middle cerebral artery (96.4%); a majority also use the anterior cerebral artery and/or the terminal internal cerebral artery or distal internal cerebral artery (71.4%). Fewer sites use the posterior cerebral artery (35.7%) or the basilar artery (14.3%). In 7.1% of sites, the radiologist determines which vessels to use during the exam. TCD screening is ordered for children with SCA annually in 92.9% of sites and every 6 months in 7.1% of sites. When TCD screening indicates abnormal TAMM velocities, 85.7% of sites initiate CRCT, 7.1% initiate hydroxyurea (HU) therapy, and 3.6% initiate both HU and CRCT. For additional evaluation, an MRI/MRA is obtained at 64.3% of sites. For high conditional results, the most common action is to initiate HU (67.9%). Other responses include obtaining an MRI/MRA (46.4%) and/or repeating the TCD in 2-4 weeks (25.0%), 6-8 weeks (35.7%), or 12-16 weeks (7.1%). Results deemed inadequate led to repeating the TCD in 2-12 weeks (57.1%) or in one year (3.6%), obtaining an MRI/MRA (57.1%), beginning HU therapy (7.1%), or no repeat TCD or change in management (3.6%). Actions for low conditional results include repeating the TCD (71.4%), obtaining an MRI/MRA (32.3%), and/or initiating HU therapy (57.1%). Surprisingly, sites use different TAMM ranges to characterize the normal/abnormal findings (Table 1). Conclusions: Nearly all DISPLACE sites order TCD screening annually, as recommended in the guidelines, with some ordering screening more frequently. A few sites did not report initiation of CRCT per STOP protocol for abnormal TCD results; however, over half of the sites reported following up with an MRI/MRA, which may suggest evaluating for vasculopathy prior to CRCT. Some sites reported beginning HU therapy for abnormal results; this may reflect consideration of patients for whom CRCT is not possible, but data were not collected for confirmation. Interestingly, results suggest a reliance on MRI/MRA since sites commonly reported ordering neuroradiology studies for abnormal, conditional, and inadequate TCD results. This may suggest an unclear pathway for children with borderline TCD results, and an area for future study. While reported value ranges closely approximated those in the STOP protocol, results indicate sites conducting screening with TCDi may use more conservative values than the validated protocol. Disclosures Phillips: NHLBI: Research Funding. Mueller:NHLBI: Research Funding. Schlenz:NHLBI: Research Funding. Melvin:NHLBI: Research Funding. Adams:NHLBI: Research Funding. Kanter:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sancilio: Research Funding; NHLBI: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Apopharma: Research Funding; ASH: Membership on an entity's Board of Directors or advisory committees.

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Splenomegaly in Children with Sickle Cell Anemia Receiving Hydroxyurea in Sub-Saharan Africa

Blood ◽

10.1182/blood-2019-129937 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 993-993

Author(s):

Leon Tshilolo ◽

George A. Tomlinson ◽

Patrick T. McGann ◽

Teresa S. Latham ◽

Peter Olupot-Olupot ◽

...

Keyword(s):

Board Of Directors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Growth Parameters ◽

Sub Saharan Africa ◽

Advisory Committees ◽

Splenic Enlargement ◽

Hydroxyurea Treatment ◽

Lower Blood ◽

Sub Saharan

Introduction. Children with sickle cell anemia enrolled in Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) received open-label hydroxyurea at maximum tolerated dose (MTD) in four countries within sub-Saharan Africa (Tshilolo et al, NEJM 2019;380:121-131). Unlike children in the United States or Europe, a substantial proportion of REACH participants had splenomegaly at enrollment, and more developed splenomegaly while receiving hydroxyurea. Splenic enlargement in association with hydroxyurea treatment in sub-Saharan Africa is previously unrecognized, and its causes and consequences remain unclear. Methods. Palpable splenomegaly was evaluated at both the mid-clavicular and mid-axillary lines at each scheduled and unscheduled sick visit. The size of the spleen, defined as the greatest distance (cm) below the subcostal margin, was recorded in the REDCap trial database at all four clinical sites. Cross-sectional analysis was performed at baseline enrollment using four spleen categories (Not Palpable, 1-4 cm, ≥5 cm, or Splenectomy) with correlations for age, sex, site, growth parameters, alpha-thalassemia trait and G6PD deficiency. This analysis was repeated using the largest spleen size over the first two years on hydroxyurea, but examining two-year laboratory values and also the hydroxyurea dose at MTD, time to MTD, dose-limiting toxicities, and clinical outcomes including acute splenic sequestration, malaria infections, and sepsis. Results. A total of 606 children started hydroxyurea study treatment, including 6 (1.0%) with previous splenectomy, 59 (9.7%) with previous splenic sequestration, and 99 (16.3%) with palpable splenomegaly at enrollment (52 children with 1-4 cm and 47 with ≥5 cm). Large spleens (≥5 cm) were commonly observed at baseline at all clinical sites except Uganda, which identified only 1 child. Compared to those with no palpable spleen, children with large spleens at baseline had similar age and growth parameters, but were significantly more likely to have alpha-thalassemia (78.7% versus 56.2%, P=0.004) and also G6PD deficiency among males (28.0% versus 17.6%, P=0.32). Children with large spleens at enrollment also had a lower hemoglobin (Hb = 6.5 versus 7.3 g/dL, P<0.001) and lower platelet count (platelets = 227 versus 410 x 109/L, P<0.001), but equivalent fetal hemoglobin (HbF = 10.2 versus 9.4%, P=0.82). On hydroxyurea treatment with escalation to MTD, 262 children (43.7%) had palpable splenomegaly recorded, including 120 (20.0%) with spleens ≥5 cm. These large spleens were observed at all four clinical sites, with DRC having the most (52) and Uganda with the least (14). After 24 months of hydroxyurea treatment, laboratory differences were noted according to the cumulative occurrence of splenomegaly including a significantly lower hemoglobin and platelet count, higher absolute reticulocyte count, and lower hydroxyurea dose at MTD (Table). Large spleens were associated with a high cumulative incidence of laboratory dose-limiting toxicities, as well as a significantly higher risk of having clinically symptomatic malaria and receiving blood transfusions (Table). A total of 31 children (5.2%) on hydroxyurea treatment received elective splenectomy, including one partial splenectomy using arterial embolization. Conclusion. Children with sickle cell anemia living in sub-Saharan Africa have an increased risk of having palpable splenomegaly, which is further increased while receiving hydroxyurea treatment. Large spleen at baseline were associated with lower blood counts, consistent with hypersplenism. On hydroxyurea treatment, children with large spleens had significantly lower blood counts and more dose-limiting toxicities, which lowered their eventual hydroxyurea dose at MTD but still led to robust HbF responses. Children with large spleens were also at higher risk of developing malaria infections, receiving transfusions, and requiring surgical splenectomy. Splenic enlargement in association with hydroxyurea treatment was common in children with sickle cell anemia in the REACH trial; its cause remains unclear but the consequences include substantial laboratory toxicity and clinical morbidity. Investigating the etiologies and management of children with chronically enlarged spleens is crucial before expanding hydroxyurea access across Africa for sickle cell anemia. Disclosures Ware: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Other: Research Drug Donation; Nova Laboratories: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: DSMB; Agios: Membership on an entity's Board of Directors or advisory committees; Addmedica: Other: Research Drug Donation.

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Sickle Stroke Screen: A Patient-Centered Educational Initiative for Children with Sickle Cell Anemia in the Displace Consortium

Blood ◽

10.1182/blood-2020-141963 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 43-44

Author(s):

Alyssa M Schlenz ◽

Shannon Phillips ◽

Martina Mueller ◽

Cathy L Melvin ◽

Robert J Adams ◽

...

Keyword(s):

Needs Assessment ◽

Board Of Directors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Stroke Prevention ◽

Stroke Risk ◽

Advisory Board ◽

Educational Initiative ◽

Advisory Committees ◽

Board Membership

Introduction: The NHLBI funded Dissemination and Implementation of Stroke Prevention Looking at the Care Environment (DISPLACE) study was designed to improve implementation of stroke prevention guidelines in children with sickle cell anemia (SCA), particularly implementation of transcranial Doppler (TCD) ultrasound for identifying individuals at risk of stroke. The study consists of 3 phases: 1) evaluating current stroke risk screening practices, 2) exploring barriers and facilitators to guideline implementation (needs assessment), and 3) designing and implementing interventions to improve stroke risk screening. A key barrier identified through qualitative methods during the needs assessment was a gap in education, including an overall lack of understanding among patients and caregivers of the purpose of TCD screening. This abstract describes the process of developing one of the interventions for phase 3, a rebranding and educational initiative. Methods: During the needs assessment, 27 key informant interviews and 173 complete surveys were conducted with individuals with SCA and their caregivers. Transcripts from the interviews and survey responses were reviewed to better understand the extent of educational gaps described by families as well as to guide initial rebranding prototypes. Prototypes were developed by the study team, including a new name and logo for TCD as well as an infographic. An interview guide was then created to obtain feedback on the prototypes from individuals with SCA and/or the parent or primary caregiver from two sites in the consortium. Cue cards with prototypes were included with prompts for the "think aloud" method to be applied during interviews. Cue cards were presented first with prototypes for the new name in black font on a white background to solicit feedback on the wording alone. Then, cue cards included various layouts, fonts, and graphics with the prototype names for in-depth feedback on the logo appearance. Finally, participants were asked questions pertaining to the infographic. Results: Twenty interviews were conducted with individuals with SCA and/or the parent/caregiver at two DISPLACE sites. Almost all participants (95%) made the connection between the wording prototypes and TCD without prompting. Many participants expressed that the word "stroke" in both options was "scary," and sometimes chose the option that was "less scary to them." However, many participants also felt that the word "stroke" was necessary to explain the reason for the procedure and would prompt families to ask about the screening as opposed to making them more fearful. The majority of participants (60%) chose "Sickle Stroke Screen" over "Stroke Risk Screen." Participants reported preferring this wording because it is specific to SCA, was easier to remember and represented a less "scary" option. The most commonly preferred logo is presented in Figure 1. Participant reasons for selecting this option were: it is easier to read; they preferred the stacked layout; it is less spread out; they liked the bold letters; it is more eye catching; and it includes the words "sickle cell" in the logo. When asked about preferences for an infographic, the majority described including a picture of a brain. Nearly all participants believed a reassuring message was needed to balance out the fear of the word "stroke." The message, "knowledge is power" provided this balance and resonated with nearly all participants (95%). Figure 2 presents the infographic developed based on participant feedback. Conclusions: Results from this educational rebranding effort highlight the importance of understanding patient and family educational gaps and incorporating their perspective and feedback into educational campaigns. The new logo and infographic were integrated into an educational pamphlet, informative posters and other material designed by the DISPLACE site principal investigators. Part 3 of the study is underway including implementation of the educational initiative at the DISPLACE sites. The new terminology and logo have also been broadly distributed throughout the US through community-based organizations to other patients, families, and stakeholders. Disclosures Kanter: AGIOS: Membership on an entity's Board of Directors or advisory committees; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; Wells Fargo: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; bluebird bio, inc: Consultancy, Honoraria; Novartis: Consultancy; Sanofi: Consultancy; Medscape: Honoraria; Guidepoint Global: Honoraria; GLG: Honoraria; BEAM: Membership on an entity's Board of Directors or advisory committees.

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