Sickle Cell Disease Pts Research Articles

A Patient-Centric Approach to Sickle Cell Disease Clinical Trials: Integrating Patient Perspectives in the RISE UP Phase 2/3 Trial of Mitapivat for Informed Protocol Design and Associated Patient Community Benefit

Background: Sickle cell disease (SCD) is a genetic blood disorder that affects millions of people worldwide. There are currently limited treatment options and a high unmet need; new therapies - and therefore new trials - are essential. Although there is evidence of growing patient (pt) participation in the drug development processes, there is a lingering suspicion among the community that they are not treated as equal partners and too frequently regarded as mere data sources. Involving pts in planning and execution of clinical trials is essential to improve participation and meet the real needs of the patient community. Mitapivat is a first-in-class, oral, allosteric activator of pyruvate kinase (PK), approved by the United States Food and Drug Administration for the treatment of hemolytic anemia in adults with PK deficiency, by the European Union European Medicines Agency, and the Medicines and Healthcare products Regulatory Agency in Great Britain for the treatment of PK deficiency in adults. The RISE UP phase 2/3 trial (NCT05031780) of mitapivat in pts with SCD was therefore devised to use a new approach to clinical trial design and recruitment that considered pt preferences wherever possible. Objective: Using the RISE UP Phase 2/3 trial, redefine best practices in clinical trial design by asking pts with SCD to describe what matters most to them in a trial setting and by involving them in decision making processes and trial awareness communications. Methods: Nine SCD pts and advocates (five from the US, one from Bahrain, one from France and two from the UK) took part in a series of clinical trial design workshops. Four remote advisory board interviews were held with pts (>16 years of age) and advocates to consult on the RISE UP Phase 2/3 clinical trial design. The insights gained from these consultations were incorporated into the proposed trial protocol design that was subsequently shared with Health Authorities (HAs) for their comment from a regulatory perspective. Once finalized, feedback from HAs was presented to the steering committee to determine whether changes requested by HAs met the needs and barriers-to-uptake expressed during partner consultations. In addition, a group of seven patients were involved in the development of the RISE UP phase 2/3 clinical trial awareness campaign, which sought to educate the community about the RISE UP clinical trial and value of pt participation. Results: Pt contributions to the protocol design included modified inclusion/exclusion criteria and the addition of pain (beyond pain crises) and fatigue as study outcomes. An overview of the community feedback is shown in Table 1. In response to pt input, monthly study visits were implemented for seven months, followed by visits every three months. An open label extension period was also added with visits on the second, fourth, eighth, and twelfth weeks of the extension period, followed by every 3 months up to 1.5 years and every six months thereafter. Taking additional pt input into account, the trial was adjusted to include a recommendation for tailored management of SCD pain crises using a daily diary. Additionally, following patient recommendations, the trial approved reimbursement for study-related travel, lodging, and specific non-study assessments. The RISE UP communications campaign was effective, with heightened interest in clinical trial participation generated within the community. Strong social media engagement and digital efforts resulted in increased trial website views, and community education and awareness efforts resulted in increased clinicaltrials.gov views to an average of 2-3 clicks per day. Approximately 278,000 users visited the RISE UP website and the campaign's YouTube video, which launched on World Sickle Cell Day has attracted 3 million views since Q4 2022. Conclusion: To meet the needs of the SCD pt and caregiver community and advance clinical trial research, we implemented a patient-centered approach to clinical trial protocol design and trial recruitment. Overall, this patient-centric approach could be useful in improving community engagement, designing trials that better reflect the needs and concerns of the pt population, and ultimately improving pt participation and diverse representation in clinical trials.

Efficacy, Safety, and Biomarker Analysis of 5 Mg and 7.5 Mg Doses of Crizanlizumab in Patients with Sickle Cell Disease: Primary Analyses from the Phase III STAND Study

Background: Crizanlizumab, a selective, humanized immunoglobulin G2 kappa anti-P-selectin monoclonal antibody, demonstrated positive clinical activity and general tolerability in patients (pts) aged ≥16 years (yrs) with sickle cell disease (SCD) in a phase II SUSTAIN trial at a dose of 5 mg/kg when compared to placebo (PBO). This primary analysis (cutoff: August 31, 2022) from the ongoing multicenter (at 65 sites in 21 countries), Phase III STAND study (NCT03814746) included the comparison of the efficacy, safety, and expression levels of biomarkers, of crizanlizumab (5 & 7.5 mg/kg) vs PBO, over 1-year post randomization, in adolescent and adult pts with SCD. Method: Pts aged ≥12 yrs, with a history of ≥2 vaso-occlusive crises (VOCs), with/without concomitant treatment with hydroxyurea/hydroxycarbamide were randomized (1:1:1) to receive intravenous crizanlizumab 5 mg/kg, 7.5 mg/kg, or PBO, on Day 1 of weeks (wks) 1 and 3, followed by every 4 wks in addition to standard of care therapy. Adverse events (AEs) were evaluated based on MedDRA version 25.1 and severity on CTCAE v5.0. Levels of biomarkers such as soluble P-selectin (sPsel), were evaluated. Results: Overall, 252 SCD pts were enrolled: 85, 84 & 83 pts received PBO, crizanlizumab 5 & 7.5 mg/kg respectively. Mean (SD) age of pts was 27.8 (12) yrs, 54 (21.4%) were adolescents, and 139 (55.2%) were females. Treatment was discontinued in 27 (31.8%), 18 (21.4%), and 15 (18.1%) pts in PBO, crizanlizumab 5 & 7.5 mg/kg arms, respectively, primarily due to pts' (n=30) and physicians' decisions (n=8). Protocol deviations (n=97) were comparable across all arms; deviations due to COVID-19 (n=80) were mostly attributed to missed visits and assessment/procedure changes during lockdown/quarantine of pts. Rate ratios of adjusted annualized rates of VOCs leading to healthcare visits, with crizanlizumab 5 & 7.5 mg/kg vs PBO, were 1.08 (95%CI: 0.76, 1.55; P>0.999) and 0.89 (95%CI: 0.62, 1.27; P>0.999), respectively, indicating no statistically significant difference (Table 1A). Mean (SD) annualized rates of VOCs leading to healthcare visits were similar across PBO (2.1 [2.8]), 5 mg/kg (2.5 [3.0]), and 7.5 mg/kg (1.9 [2.3]) arms. Rate ratios of the adjusted annualized rates of VOCs managed at home and/or leading to a healthcare visit, with crizanlizumab 5 & 7.5 mg/kg vs PBO, were 1.21 (95%CI: 0.87, 1.70) and 0.83 (95%CI: 0.59, 1.17), respectively, suggesting no statistically significant difference (Table 1B). Overall, AEs were reported in 77 (90.6%), 74 (88.1%), & 77 (92.8%) pts with PBO, crizanlizumab 5 & 7.5 mg/kg, respectively (Table 2), the most common being, pyrexia (22 [25.9%], 22 [26.2%], 19 [22.9%]), COVID-19 (17 [20.0%], 18 [21.4%], 27 [32.5%]), and headache (16 [18.8%], 21 [25.0%], 13 [15.7%]). Serious AEs (SAEs) and grade ≥3 AEs were less frequent with PBO (30.6%, 31.8%) and crizanlizumab 7.5 mg/kg (26.5%, 38.6%) than with 5 mg/kg (41.7%, 56.0%). Among AEs of special interest, infections, and infusion-related reactions (all categories) were the most frequent (Table 2). Treatment-related SAEs and AEs leading to discontinuation were rare (<4% pts, all arms). None of the 6 fatal SAEs were related to treatment. Levels of free and total sPsel were measured across time: At Wk 3 Day 1, free sPsel showed a relative change from baseline in geometric mean (CV%, range) of 1.01 (56.2, 0.201-7.37) with PBO vs 0.05 (88.9, 0.00507-0.225) and 0.06 (68.4, 0.0146-0.208) with 5 & 7.5 mg/kg doses, respectively. Relative change from baseline in total sPsel remained close to 0% in the PBO arm at different study visits, while it increased in treatment arms from Wk 3 Day 1 onward, plateauing at Wk 15 Day 1. Conclusion: Unlike the previous phase II PBO-controlled SUSTAIN study, the STAND study did not demonstrate superiority of crizanlizumab (5 or 7.5 mg/kg) over PBO on its primary and key secondary efficacy endpoints, in pts aged ≥12 yrs. These results differ from the previous study results and may be due to various factors, such as geographic differences in healthcare utilization as well as the low VOC rates in all arms, possibly either due to selection of pts with less severe disease, or, more likely due to the lower reporting of VOCs during the pandemic. The safety results were consistent with the known safety profile of crizanlizumab in SCD pts with no new safety concerns. Both treatment arms showed reductions in free sPsel vs PBO, demonstrating crizanlizumab activity on this biological parameter.

PB2224: IMPACT OF COVID-19 PANDEMIC ON PATIENTS WITH SICKLE CELL DISEASE: RESULTS FROM THE REAL WORLD ASSESSMENT SURVEY FOR SICKLE CELL DISEASE IN SAUDI (ROARS)

Background: Sickle cell disease (SCD) is a chronic hemolytic disease with multisystem involvement leading to significant morbidities and mortalities. SCD confers a significant burden on patients (pts), including a high impact on quality of life (QoL). The impact of the COVID-19 pandemic on pts with SCD has not been well characterized. Aims: The Real World Assessment Survey for Sickle Cell Disease in the Kingdom of Saudi Arabia (KSA) (ROARS) is a cross-sectional survey of pts with SCD and treating healthcare professionals (HCPs), which was designed to understand several aspects of the burden of SCD in KSA. In this study, we examined the impact of the COVID-19 pandemic on SCD pts based on findings from ROARS. Methods: Between September and December 2021, pts with SCD (age: 5-65 years) and HCPs (>2 years SCD experience, SCD load >50 pts, >50% of clinical practice time spent treating SCD pts) were surveyed (in person or via caregiver if pts were between 5-14 years of age) using the structured, bilingual ROARS questionnaires (English/Arabic) through personal quantitative web-assisted telephone interviews. ROARS was developed by SCD experts from KSA and Novartis, and includes the global health domain of Patient-Reported Outcomes Measurement Information System (PROMIS), a validated tool for assessing QoL among SCD pts and caregivers of different age ranges. Questions covered topics such as disease impact on QoL, symptoms, disease complications, treatment goals, treatment strategies, and COVID-19. Descriptive statistics were used to summarize the results. Results: A total of 1011 pts (pediatric: n=504; adult: n=507) and 64 HCPs (hematologists: n=31; non-hematologists: n=33) completed the survey. Data were collected from 11 cities, with 90% of respondents from Eastern and South-Western provinces of KSA where the SCD prevalence is highest. The top 5 complications reported by both pediatric and adult pts were fever (52%), joint issues (49%), swollen and/or painful fingers/toes (47%), infections (37%), and tight chest pain (35%). A high proportion of pts (80%) felt that the pandemic had an impact on their medical care (Figure) (adults: 85%;[PM(1] pediatric: 76%). The impact of COVID-19 on medical care was particularly evident in pts treated with hydroxyurea compared to untreated pts (adults: 91% and 79%; pediatric: 84% and 74%). When survey results were stratified by the number of vaso-occlusive crises (VOCs), 85% of adult pts reported an impact of the pandemic on their medical care, regardless of the VOC frequency (<5 or ≥5); among pediatric pts, 72% with ≥5 VOCs and 83% with <5 VOCs reported an impact. Mental/emotional impact of the pandemic was reported by 66% of pts (adults: 68%; pediatric: 64%). The majority of pts missed or cancelled their appointments due to COVID-19 (adults: 81%; pediatric: 74%). Overall, 39% of the pts reported the impact of the pandemic as severe (Figure). From the HCPs’ perspective, 86% felt that COVID-19 affected their medical service, and 78% thought it affected their pts’ mental/emotional well-being. Overall, 16% of HCPs thought the pandemic significantly impacted their pts. Image:Summary/Conclusion: The ROARS survey among Saudi pts with SCD found that the majority of pts, especially adults, felt the COVID-19 pandemic had an impact on their medical care and emotional well-being. The impact of COVID-19 was also reflected in a decline in pt care, as reported by HCPs. In future, it would be interesting to understand the impact of the pandemic on vaccinated vs unvaccinated SCD pts.

Rare Cases of Infusion-Related Reactions (IRRs) Presenting As Pain Events during or after Crizanlizumab Infusion in Patients (Pts) with Sickle Cell Disease (SCD): A Systematic Evaluation of Post-Marketing (PM) Reports

Rare Cases of Infusion-Related Reactions (IRRs) Presenting As Pain Events during or after Crizanlizumab Infusion in Patients (Pts) with Sickle Cell Disease (SCD): A Systematic Evaluation of Post-Marketing (PM) Reports

Experiences of Sickle Cell Disease (SCD) Reported By Healthcare Professionals (HCPs) across Different Regions: International Sickle Cell World Assessment Survey (SWAY)

Experiences of Sickle Cell Disease (SCD) Reported By Healthcare Professionals (HCPs) across Different Regions: International Sickle Cell World Assessment Survey (SWAY)

Real-World Data on the Occurrence of Vaso-Occlusive Crises (VOCs) in Patients with Sickle Cell Disease (SCD) and a High Baseline Disease Burden Treated with Crizanlizumab: Results from a Managed Access Program (MAP)

Real-World Data on the Occurrence of Vaso-Occlusive Crises (VOCs) in Patients with Sickle Cell Disease (SCD) and a High Baseline Disease Burden Treated with Crizanlizumab: Results from a Managed Access Program (MAP)

An Age Analysis of the International Sickle Cell World Assessment Survey (SWAY), Focusing on Symptoms, Treatment Goals and the Impact of SCD on Patients' Daily Lives

An Age Analysis of the International Sickle Cell World Assessment Survey (SWAY), Focusing on Symptoms, Treatment Goals and the Impact of SCD on Patients' Daily Lives

Rheologic Assessments of Sickle Cell Patients Post Allogeneic Hematopoietic Cell Transplant

<h3>Introduction</h3> Red blood cell (RBC) rheology is markedly abnormal in sickle cell disease (SCD) and is associated with clinical complications. Even fully oxygenated, sickle RBC are less deformable than those of HbAA or HbAS individuals; upon deoxygenation, deformability further declines. The goal of any cell-based therapy of curative intent should be to normalize SCD RBC rheology. We propose to functionally assess a series of post-allogeneic hematopoietic cell transplant (alloHCT) patients (pts) with SCD using rheological biomarker measurements of deformability and sickling to determine if the rheology has been normalized. <h3>Methods</h3> Blood from 6 SCD pts post-alloHCT were analyzed using an ektacytometer with oxygenscan (Lorrca) to measure RBC deformability (elongation index EI), under a range of pO₂ (150-0 mmHg). EImax is the deformability of the oxygenated sickle RBC; EImin is the deformability of deoxygenated RBCs. The point of sickling (PoS) is the pO₂ at which RBC deformability rapidly declines. Reference ranges were generated using n=45 HbSS samples age 2-21, on hydroxyurea, chronic transfusion, or untreated; n=14 HbAS, and n=43 HbAA. <h3>Results</h3> Figure 1 shows measurements obtained on 5 pts post alloHCT with a range of donor chimerism, as well as typical values for HbAA, HbAS, and HbSS. Pts 1 and 3 exhibit normal rheology; both were transplanted with an HbAA donor, had high chimerism and no detectable HbS. Pt 2 had 40% whole blood chimerism and hbS < 50%, yet their plot resembles that of untransplanted HbSS. Pts 5 and 6 exhibit rheology in the HbAS range; they have intermediate chimerism from an AS donor. Pt 2 is the only subject with values in the HbSS range, and the only subject with SCD symptoms. Clinical details and biomarker values for all 6 analyzed are in Table 1, as well as ranges of rheological values for HbSS and HbAS pts generated in the Sheehan and Shevkoplyas labs. <h3>Conclusions</h3> Current HCT evaluation depends on chimerism and hemoglobin profiles, and do not assess RBC function. Using the Lorrca with oxygenscan, we identified a post-alloHSCT patient with rheological values consistent with an HbSS patient despite donor chimerism >20% and HbS <50% thought sufficient for cure from an HbAA donor. Our results suggest that this functional analysis may help with management post-alloHCT and may be essential in assessing new gene-based therapy approaches to curing pts with SCD.

Rheological Assessments of Sickle Cell Patients Post Allogeneic Hematopoietic Cell Transplant

Introduction: Mixed donor chimerism (MDC) occurs in nearly 35% of patients with sickle cell disease (SCD) post allogeneic hematopoietic cell transplant (alloHCT). Donor myeloid engraftment of &amp;gt;20% is considered necessary to support disease resolution. However, in a disease known for its clinical variability, we hypothesize that patients (pts) with a severe pre-HCT phenotype may have abnormal RBC rheology at a level of chimerism and %HbS believed to be consistent with a cure. RBC rheology is markedly abnormal in SCD; these abnormalities are associated with SCD related clinical complications. Even fully oxygenated, sickle RBC are less deformable than those of HbAA or HbAS individuals; upon deoxygenation, deformability further declines. Sickle RBC morphology reflects the tendency to polymerize, with characteristic sickle forms. Sickle RBC are more adherent to the endothelial cell lining of the vasculature than HbAA or HbAS RBCs. The goal of any cell-based therapy of curative intent should be normalize the red cell rheology. To determine if the rheology of blood from SCD pts post-HCT with varying degrees of donor chimerism fall into the HbSS range of values, we propose to functionally assess the peripheral blood from a series of 6 post alloHCT SCD patients using a battery of rheological tests measuring deformability, sickling, adherence, percent dense cells (%DRBC), and RBC morphology. Methods: Peripheral blood samples (EDTA) from 6 SCD pts post alloHCT with a matched sibling donor were collected and immediately analyzed using oxygenscan (Lorrca), artificial microvascular network (AMVN), microfluidic image acquisition, and an ADVIA hematology analyzer. The Lorrca with oxygenscan measures RBC deformability (elongation index EI), under a range of pO2 (150-0 mmHg). EImax is the deformability of the oxygenated sickle RBC; EImin is the deformability of deoxygenated RBCs. The point of sickling (PoS) is the pO2 at which RBC deformability rapidly declines. RBC adhesiveness is measured by the difference in rate of perfusion of RBC through the AVMN coated with adhesive proteins (adherent AVMN) and a non-adherent, uncoated AVMN. %DRBC was measured by an ADVIA hematology analyzer. Microscopic RBC images were acquired and classified to determine the fraction of sickled RBCs in well-oxygenated samples. Additional clinical data including Hb profile, donor chimerism, and symptoms were obtained via chart review. Reference ranges were generated as described above using n=45 HbSS samples ages 2-21, on hydroxyurea, chronic transfusion, or untreated; n=14 HbAS, and n=43 HbAA. Results: In Figure 1, we show the measurements obtained by the Lorrca with oxygenscan on 5 pts post-alloHCT with a range of donor chimerism, as well as typical values for HbAA, HbAS, and HbSS patients. Patient 1 and 3 exhibit normal rheology; both were transplanted with a HbAA donor, with high chimerism and no detectable HbS. Patient 2 has 40% whole blood chimerism, well above the 20% threshold described with myeloid chimerism, and a HbS less than 50%, yet their plot resembles that of an untransplanted HbSS pt; the donor to Patient 2 exhibits the expected HbAA deformability. Patients 5 and 6 exhibit rheology in the HbAS range; they have intermediate chimerism from a HbAS donor. Clinical details and biomarker panel values for all 6 pts analyzed are in Table 1, as well as ranges of values for HbSS and HbAS subjects generated in the Sheehan and Shevkoplyas labs. Patient 2 is the only subject with values in the HbSS range, and the only subject with SCD symptoms. Conclusions: Our rheological tests identified a pt with values consistent with a HbSS pt of moderate severity or treated with hydroxyurea despite variable donor chimerism above the 20% threshold and HbS &amp;lt;50% thought to be sufficient for cure. The pt reported pain events beginning two years prior, indicating a clinical correlation supporting the validity of the rheological tests we propose to use to distinguish cure from persistent SCD. Current post-HCT evaluation depends on chimerism and hemoglobin profiles, and would not detect the significant functional abnormalities visible by Lorrca with oxygenscan biomarkers that indicate that Patient 2 is at risk for SCD related complications. Our results suggest that this functional analysis may help with management of post alloHCT SCD pts, and may be even more essential to assessing new gene-based therapy approaches to curing patients with SCD. Disclosures Rab: RR Mechatronics: Research Funding. van Wijk:Agios Pharmaceuticals: Consultancy, Research Funding; RR Mechatronics: Research Funding. Shevkoplyas:SSS: Research Funding; New Health Sciences: Consultancy.

197 Annual Hospitalization and Mortality Trends Among Patients With Sickle Cell Disease and Clostridioides difficile Infection

INTRODUCTION: Frequent hospitalizations, antibiotic exposure, dysbiosis and impaired immune function associated with Sickle Cell Disease (SCD) predisposes pts to Clostridioides difficile infection (CDI). As a result, we hypothesize that the incidence of CDI in those with SCD has been increasing in the United States and that those with SCD and CDI have worse outcomes. METHODS: Using ICD-9 codes within the National Inpatient Sample Database, we identified pts between 2005–2012 with SCD. For each pt, we obtained various factors (e.g., demographics, medical co-morbidities and outcomes), grouped them as SCD and CDI (SCD + CDI) or those with SCD without CDI (SCD − CDI) and statistically compared. Using propensity score matching, SCD + CDI pts were matched with SCD − CDI in 1:1 ratio. All categorical variables were compared with Pearson's χ2 test and continuous variables were analyzed with paired t-test (SAS 9.4, Cary, NC). RESULTS: Among 747,127 hospitalized pts with SCD, 804 (0.1%) had SCD + CDI. SCD + CDI were more likely to be African Americans (88.0% v 32.7%, P &lt; 0.0001), smokers (10.5% v 7.1%, P &lt; 0.0001), and had a higher association with HIV (2.2% v 0.9%, P = 0.0001), Hepatitis C (1.6% v 0.8%, P = 0.007), chronic liver disease (6.0% v 2.8%, P &lt; 0.0001), cholelithiasis (4.0% v 2.2%, P &lt; 0.001), acute pancreatitis (2.5% v 1.4%, P &lt; 0.0001) and chronic pancreatitis (2.0% v 0.6%, P &lt; 0.0001). SCD + CDI were less likely to be associated with atrial fibrillation (4.9% v 15.1%, P &lt; 0.0001), CHF (13.9% v 18.5%, P = 0.001) and hypothyroidism (3.7% v 9.4%, P &lt; 0.0001). SCD + CDI had significantly higher complication rates including acute chest syndrome (4.4% v 1.8%, P &lt; 0.0001), splenic sequestration (1.6% v 0.3%, P &lt; 0.0001), and vaso-occlusive crises (2.7% v 1.4%, P &lt; 0.0001). Though prematch inpatient mortality was not different between the two groups (5.9% v 6.5%, P = 0.43), SCD + CDI pts had significantly higher inpatient mortality than SCD − CDI pts after match (5.6% v 3.3%, P = 0.04). Over time, we noted increases in hospitalization-requirement and inpatient mortality for SCD + CDI pts (Tables 1 and 2). CONCLUSION: Ours is the largest study exploring the association of CDI in SCD patients. Hospitalization rates and mortality rates for hospitalized SCD pts with CDI has been rising in the United States and it seems that hospitalized SCD pts with CDI are more likely to develop SCD related complications and have a higher mortality. In SCD+CDI pts, clinicians should consider more aggressive initial treatment to minimize these poor outcomes.

A Polymorphism in Toll-like Receptor 2 Gene Is Associated with Occurrence of Bacterial Infections in Sickle Cell Disease Patients

Background: Sickle cell disease (SCD) patients (pts) are at increased risk of infection. This susceptibility is partially explained by the loss of spleen function, but other factors such as inflammatory status might also play a role. Despite adequate immunization and antimicrobial prophylaxis, bacterial infection remains a major cause of morbidity and mortality in SCD pts. Toll-like receptors (TLR), transmembrane proteins that recognize a wide range of pathogen molecular patterns, are key receptors in innate immune response. The association among TLR and infections in SCD has scarcely been explored.Objective: To analyze if functional polymorphisms in TLR genes can modulate the susceptibility to bacterial infections in SCD pts.Methods: Case-control retrospective study; 430 SCD pts followed in university hospitals in Brazil (n=196), France (n=180, mainly from Subsaharan Africa and French West Indies) and Senegal (n=54) were included. Sites of bacterial infection were lower respiratory system, abdominal, upper urinary system, bone/joints, central nervous system, blood stream, or any site for tuberculosis. For pts who underwent hematopoietic stem cell transplant (HSCT), only bacterial infections before HSCT were considered. All pts were tested for 7 single nucleotide polymorphisms (SNP) in TLR-1(rs4833095), TLR-2 (rs4696480, rs3804099, rs3804100), TLR-6 (rs5743810) and TLR-10 (rs11466653, rs11096957) using TaqMan 5'-nuclease assay. Univariate analysis was performed with chi-square or Mann-Whitney for categorical and continuous variables respectively. Associations were measured by odds ratio (OR). For SNP associations, significant P-value corrected by Bonferroni (cP) was 0.007; for genetic models, cP was 0.01.Results: Median age of cohort was 30 years (range: 2-70) and 87% were ≥18 years; 57% of pts were female. SCD genotype was SS in 81%, SC in 11%, SB in 7% and other in 1%. Fifty-eight percent received hydroxyurea and 79% received red blood cell transfusions; seven pts underwent HSCT. Eleven pts died during follow-up, mostly from acute chest syndrome and hemorrhagic stroke. All pts had access to immunization against encapsulated bacteria and to penicillin prophylaxis. One hundred ninety-five pts (45%) did not present any bacterial infection, whereas 235 (55%) pts presented at least one episode of bacterial infection, of which 20% had ≥ 3 episodes. Bacterial infections were mainly respiratory (51%), bone/joints (23%) and urinary (20%). In 106 cases, etiological agents were identified; most common agents were Escherichia coli, Streptococcuspneumoniae, Mycobacterium tuberculosis and Salmonella spp. In univariate analysis, there was no association among occurrence of infections and gender, origin and age distribution. Gene analysis: all tested SNPs had a typing rate >90% and minimum allele frequency >1%. The TLR-2 SNP rs4696480 (n=425) showed significant association with infection (p<0.001). Next, we tested genetic models for this association. Distribution of rs4696480 genotypes was: infected - AA=35%, TA=50%, TT=15%; non infected - AA=28%, TA=67%, TT=5%. In the overdominant model, the heterozygous genotype (TA) occurred significantly more in non infected (67%) than in infected pts (50%) compared with TT+AA (OR 0.5, 95%CI 0.34-0.75, P<0.001). Also, in the recessive model, genotype TT occurred significantly more in infected (15%) than in non infected pts (5%) compared with TA+AA (OR 3.18, 95%CI 1.53-6.61, P<0.001). Furthermore, in comparison with an African/African-American population described in the 1000 genomes database (n=661), TA genotype was more frequent in SCD pts, and TT genotype was significantly less frequent. Other TLR SNPs genotype and haplotype analysis did not show any significant association with occurrence of infections.Discussion: In SCD pts, TLR-2 rs4696480 TA genotype might be protective against bacterial infections, whereas TT genotype might increase risk of such infections. Previous reports demonstrated higher secretion of inflammatory factors in cells from AA individuals, lower occurrence and severity of immune diseases in T carriers. TA genotype might stand between deleterious effects of over inflammatory response (AA genotype) and under response (TT genotype) to infectious agents. DisclosuresNo relevant conflicts of interest to declare.

Assessment of Calcineurin Inhibitor-Associated Neurotoxicity in Patients with Sickle Cell Disease Receiving a Matched Sibling Donor or T-Cell Depleted Haploidentical Hematopoietic Stem Cell Transplantation

Introduction: Sickle cell disease (SCD) is one of the most prevalent monogenic hematological disorders leading to progressive multi-organ damage and reduced life expectancy despite a significant improvement of conventional and supportive care. Allogeneic hematopoietic stem cell transplantation (HSCT) with a matched sibling donor (MSD) represents currently the only curative treatment option, limited by a donor availability <20%. In a pilot study, we compared α/β/CD19 and CD3/CD19, respectively T-cell depleted haploidentical HSCT (T-haplo-HSCT) with MSD HSCT in patients (pts) with advanced stage SCD, using almost identical HSCT regimens for both donor groups.Neurotoxicity (NT) contributes significantly to HSCT-associated morbidity and mortality. Calcineurin inhibitor (CNI) related NT after HSCT is mostly caused by cyclosporine A (CsA) and tacrolimus (FK506) with an overall frequency between 4.2% - 28.8%, and severe NT in 4% - 11%, such as posterior reversible encephalopathy syndrome (PRES), seizures, visual disturbance, cortical blindness, aphasia or ataxia.Particularly in hemoglobinopathies (thalassemia, SCD) the reported incidence is around 30%, possibly also due to impaired hepatic metabolization of CsA and FK506 based on iron overload. However, also infusion modalities might impact on NT, since it was more frequently reported after 4-hours bolus injections (10.3%) than continuous infusion (3.3%). However, the excessive NT observed in SCD might be also related to the systemic vasculopathy, increasing with age and pro-inflammatory triggers after allo-HSCT.Methods: A total of 30 pts aged 3 to 31 years with homozygous SCD or HbS 0/+ ß-Thal were treated between 2012 and 2018. Nine pts received a MSD bone marrow (BM) graft, 21 pts received T-haplo-HSCT from a relative (1 second T-haplo-HSCT due to graft rejection) with a α/β CD19 or CD3/CD19 depleted graft. Post-HSCT immunosuppression consisted of either CsA in 6 MSD and 16 T-haplo-HSCT pts or FK506 in 3 MSD and 6 T-haplo-HSCT pts, both mostly in combination with mycophenolate mofetil (MMF). FK506 was administered as a 20-hours continuous infusion, while CsA was given as 4-hours bolus injections. Dosage was adjusted according to usual target levels (CsA: 120ng/ml; FK506: 7ng/ml). Duration of immunosuppression was >6 months in T-haplo-SCT and <6 months in MSD, depending on chimerism. All pts developing neurological symptoms indicative for severe CNI-related NT underwent neuroradiological imaging (MRI/CT) with consecutive symptomatic treatment as indicated.Results: Overall CNI-related NT was observed in 32.3% of our HSCT pts. Severe NT such as PRES and visual disturbance combined with aphasia was present in 16.1% (Table 1). Overall, NT was more prevalent in MSD (n=5, 55.5%) than in T-haplo-HSCT pts (n=5, 22.7%). The majority of NT events was observed under CsA prophylaxis (8/10; 80%) and in only 22% (2/9) pts with FK506. All 5 cases of severe NT, particularly all PRES, occurred on CsA. Complete recovery of neurologic symptoms was achieved in all pts spontaneously or after switching CsA to FK506 or everolimus (Table 1). Moreover, 60% of pts with NT was >18 years, and 90% >12 years suggesting an increasing risk with age while a third of patients with pre-existing NT experienced no post-HSCT NT. Of note, 4 of 5 pts with severe NT also experienced a mild acute GvHD (Table 1). The overall (OS) and disease-free survival (DFS) with a median follow-up of 17 months in T-haplo-HSCT pts and 22 months in 9 MSD HSCT pts was 90% vs. 100%, respectively.Conclusions: Our data confirm an elevated risk for NT in SCD pts following allo-HSCT. Importantly, the incidence of NT events seems to be related to age (90% of pts with NT were >12years), donor source (MSD vs. T-Haplo; 55.5% vs 22.7%) and CsA rather than FK506 (CSA 80% vs. FK506 20%). All severe NT (particularly all PRES) were observed in pts with CsA prophylaxis, while the continuous infusion of FK506 might have levelled concentration peaks. Nevertheless, the NT observed with CsA post-HSCT could be the consequence of predominantly CsA-related vascular complications inflicting systemically pre-damaged vessels of SCD pts. The mechanism of action could be similar to other systemic endotheliopathies such as sinusoidal obstruction syndrome (VOD/SOS), transplant-associated microangiopathy (TAM) and acute GvHD which was observed in 4/5 pts with severe NT, compared to an overall GvHD rate of 29%. [Display omitted] DisclosuresCorbacioglu:Gentium: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria.

Home Based Primary Care for Patients with Sickle Cell Disease

Background: Sickle cell disease (SCD) is characterized by sickled red blood cells that can cause severely painful vaso-occlusive crises. These crises can cause damage to multiple organs and bring about additional chronic disease, such as avascular necrosis, leg ulcers, pulmonary hypertension, and renal failure. While there are options for disease modification, these are not effective if patients (pts) cannot attend regular doctor visits for their condition to be monitored and for medications to be adjusted. Obstacles to obtaining outpatient primary care include physical disability, environmental factors, transportation, and psychosocial factors. Impaired access to primary care leads to poor clinical outcomes in chronic diseases, such as SCD. This study was conducted to help pts with SCD who had the most barriers to obtaining outpatient primary care.Home based primary care has proven beneficial for pts with chronic illnesses in the past. Utilizing this method, a physician meets with pts in their homes to manage both acute and chronic illnesses. This eliminates many potential barriers for pts with difficulty attending office visits and would provide continuity of care. It also allows physicians to observe other potential factors that could undermine the treatment plans for these pts, and get the correct member of the team to intervene more efficiently.Methods: Outcomes were measured for patient quality of care and health service utilization, both one year prior to and one year after the home visits began. Data was collected from a chart review and included the number of primary care visits, day hospital referrals, and emergency department visits. SCD specific immunizations and the number of prescription refills were also noted. McNemar's test and Wilcoxon signed rank test were used to compare binary and continuous outcomes, respectively, during the years prior to and after home based primary care began.Results: There were 23 SCD pts enrolled in this study, with 13 pts (69% female, 31% male) having completed one full year of home visits. These pts ranged from 26 to 66 years old. Comorbidities include one patient with a history of a myocardial infarction (MI) and two with diabetes mellitus. Other medical history noted were: acute chest syndrome (62%), thrombosis (62%), avascular necrosis (46%), retinopathy (46%), depression (38%), kidney disease (31%), hypertension (31%), pulmonary hypertension (23%), stroke (23%), and iron overload (15%). Most pts had received transfusions (92%), and 77% had taken hydroxyurea.Pts received a median number of 11 home visits (range 7-15) during the 1-year program in which they received home based primary care. The median number of new long term prescriptions increased significantly (p = 0.04) from 1 to 3. Five pts not previously receiving PVC-13 vaccine started to receive it after the initiation of the home visit program (p = 0.06). The total number of immunizations (p = 0.09), months with prescription refills (p = 0.08) both increased slightly. There was no change in the number of new short term prescriptions, breast or colon cancer screening rates, nor influenza, PVC-23, or MenAWCY immunization rates.The median number of reported vaso-occlusive crises per patient decreased from 8 per year to 5 (p = 0.69), and the median number of emergency department visits per patient decreased from 6 visits per year to 3 visits per year (p = 0.80).Conclusion: Overall, home based primary care seems to be a promising alternative for pts with SCD. It had a significant impact on patient quality of care and may improve prescription adherence, but more data are needed to determine if it has an effect on healthcare utilization for pts with SCD. DisclosuresMoore:Ohio State University College of Medicine: Research Funding. Desai:FDA: Research Funding; Pfizer: Research Funding; University of Pittsburgh: Research Funding; Selexy/Novartis: Research Funding; NIH: Research Funding; Ironwood: Other: Adjudication Committee.

Stem Cell Transplantation in Advanced Stage Sickle Cell Disease with Haploidentical T-Cell Depleted PBSC Yields Comparable Outcomes to Matched Sibling Donor Bone Marrow: Results of a Pilot Study

Background: Sickle cell disease (SCD) is an inherited disorder with an estimate of 300,000 affected newborns per year worldwide. Despite improvements in preventive measures and conventional therapy, substantial morbidity and mortality, resulting in a reduced life expectancy persist. Allogeneic hematopoietic stem cell transplantation (HSCT) with a matched sibling donor (MSD) is currently the curative standard of care. However, matched donor availability is <20% and unrelated donor (MUD) HSCT is associated with unacceptably high rates of severe graft-versus-host disease (GvHD). A T-cell depleted HSCT from a haploidentical relative (T-haplo-HSCT) expands donor availability while exhibiting low GvHD rates and thus could offer cure to the remaining 80% of SCD patients (pts).Methods: We report the results of 29 pts with advanced stage SCD transplanted with either a T-cell depleted haploidentical regimen (20 pts, median age 13 years, range 3-31 years) or with bone marrow from a matched family donor (MSD, 9 pts, median age 14, range 9-25 years). Indication for HSCT was advanced stage SCD related complications. Pts with a MSD received a bone marrow (BM) graft. Pts requiring an alternative donor were transplanted with an αß/CD19 (n=5) or CD3/CD19 (n=15) depleted graft from a haploidentical family donor. The conditioning regimen for both groups was identical except that antithymoglobulin (ATG-Neovii®) was given upfront on day -10 to -8 in T-haplo-HSCT and on day -3 to -1 in MSD. Chemotherapy consisted of thiotepa 2 x 5 mg/kg, fludarabine 4 x 40 mg/m2 and treosulfan 3 x 14 g/m2, given between days -10 and -2. Post-HSCT immunosuppression consisted of mofetil mycophenolate and tacrolimus or cyclosporine A for a duration >6 months in T-haplo-HSCT and <6 months in MSD, depending on chimerism. The MSD group received a graft containing a median of 2.4 x 108 cells/kg body weight (BW). The T-haplo-SCT group received a peripheral stem cell allograft with a median of 13.1 x 106 CD34+ cells/kg BW.Results: The conditioning regimen was well tolerated in all pts with no high-grade transplant related toxicity. The overall (OS) and disease-free survival (DFS) with a median follow-up of 17 months in 20 advanced stage mostly adolescent and adult T-haplo-HSCT pts and 22 months in 9 MSD HSCT pts was 90% vs. 100%, respectively. Engraftment was achieved in most pts with stable chimerism over 90%, except for 4 pts with a stable MC in the T-haplo SCT group and 1 patient in the MSD group off immunosuppression. All pts presented a complete BM engraftment of red cell precursors. Only one patient in the T-haplo-HSCT group with a mixed chimerism is still under immunosuppression.The post-HSCT bacterial infectious complications were comparable in both groups and the most common observed viral infections were systemic cytomegaly virus (CMV), adenovirus (ADV), polyomavirus (BKV) and Epstein Barr virus (EBV) reactivations which were successfully treated with intravenous antiviral drugs or virus specific T-cells.Two patients in the T-haplo-HSCT group achieved a DFS off immunosuppression but succumbed to post-HSCT complications. One developed a rotavirus gastroenteritis and an uncontrolled CMV pneumonitis. The other a late graft failure and succumbed to a macrophage activation syndrome.None of our pts developed a Glucksberg Grade III-IV acute GvHD and in the T-haplo SCT group 4 pts (20%) and in the MSD group 2 pts (22%) developed a steroid sensitive mild to moderate cGvHD (fasciitis/oral as well as mild cutaneous GvHD). No extensive cGvHD was observed.To our knowledge this is the largest group of advanced stage SCD pts transplanted with either a T-haplo-HSCT or a MSD approach, according to donor availability, with an almost identical regimen in a direct comparative design. These preliminary results demonstrate increasing evidence for the feasibility, safety and efficacy of a T-haplo-HSCT using CD3/CD19 or αβ/CD19 depleted grafts, in order to offer a curative option to the majority of pts with SCD. A prospective, stratified non-inferiority trial is in preparation (EudraCT number 2018-002652-33) in order to confirm these preliminary results in a large prospective cohort. DisclosuresCorbacioglu:Gentium: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria.

History of Asthma is Associated with Albuminuria within an International Pediatric Cohort of Sickle Cell Disease Patients: A Casire Group Analysis

Background: Renal disease is a common end organ complication of sickle cell disease(SCD). Risk factors of sickle cell nephropathy include age, genotype, and anemia. We have investigated and discovered Lower Hemoglobin Oxygen Saturation levels associated with microalbuminuria. To further investigate this, we investigated a patient's history of asthma as a risk factor of renal disease. Asthma has been linked to increased mortality in adult and children with SCD from the National Cooperative SCD Study Group. In our ongoing International CASIRE Renal Cohort study, we investigated the clinical history of asthma and laboratory correlates of albuminuria and proteinuria as measured by Urine Protein/Creatinine and Urine Albumin/Creatinine .Methods: 538pediatric and adult SCD (3-59 y/o) patients were recruited at baseline from 6 Centers (USA: Univ of Michigan, Case Medical Center/Rainbow Babies, Albert Einstein-Montefiore Medical Center, Univ of Connecticut; Italy: Univ. of Padova, Univ of Naples;). Clinical history and laboratory studies, including Pain crisis patterns, SBP, DBP, BMI, CBC, Serum Crt, Urine ph, Urine SG were collected. For this report, we concentrated on patient’s comorbidities and sickle cell medical history, specifically pain crisis patterns, acute chest history and asthma. Urine Microalbumin/Crt(UMA) (mg/gm) was obtained in 172 patients and we categorized patients into No Albuminuria: (No UMA)<30mg/gm and Albuminuria(UMAlbum): Microalbuminuria(MicroUMA) 30-299mg/gm and Macroalbuminuria (MacroUMA)>300mg/gm.334 subjects answered the question of medical history of asthma and of those 172 had Urine Microalbumin (UMA) levels. 75% of SCD-Asthma group (N=56) and 78% of SCD-NoAsthma group (N=204) had severe SCD (SS or SBeta Zero). Children (<18y/o) comprised 58% of the SCD-Asthma group (N=43) and 62% of the SCD-NoAsthma group (N=161). Mean age was 16 y/o in both SCD-Asthma and SCD-NoAsthma Groups.Results: No Albuminuria (NoUMAlbum) was reported in 80% (138/172) while Albuminuria(UMAlbum) was recorded in 20% (34/172) of the Cohort. Severe SCD pts represented 91% (n=33) of the Albuminuria pts. Adult UMA levels were higher (mean=61) than Peds UMA levels (mean=22) (p=0.025). Patients with History of Asthma had higher mean UMA levels ( 94 vs 21, p=0.005). Further, a history of asthma was associated with higher mean UMA levels (122 vs 23, p=0.003) within the Severe Genotype group (p=0.002), within all Pediatric SCD patients ( 60 vs 17, p=0.002), and within Severe Pediatric SCD patients ( 68 vs 19, p=0.004) (One Way Anova). Within the Medical history, BMI in the underweight range and a history of priapism were associated with elevated UMA levels.Conclusions: Age and Severe Genotype was associated with Albuminuria. A history of asthma was strongly associated with renal disease in Pediatric SCD patients in addition to a very strong association within Pediatric Severe Genotype patients. Optimal control of asthma could possibly mitigate the risk of kidney disease with SCD patients. A more in-dept analysis of patient's history of asthma would provide stronger evidence of these findings. DisclosuresAsare:Intramural University of Ghana Research fund: Research Funding; Vanderbilt University Medical Center Gift Funds: Research Funding. Piccone:Novartis: Other: Speaker. Rivers:Acetylon: Research Funding.

Comparison of Clinical Outcomes Between Adult and Pediatric Patients (pts) with Sickle Cell Disease (SCD): 3-Year (y) Follow-up in a Prospective, Longitudinal, Noninterventional Registry Trial

Introduction: Although advances in care have allowed individuals with SCD to live further into adulthood, treatment of adult SCD pts is challenging due to increased rates of comorbidities and complications. Here we present clinical outcomes and treatment patterns from a prospective registry of pediatric and adult pts with SCD at 3 y to better characterize disease and treatment patterns in adult pts.Methods: Pts ≥2 y old with HbSS, HbSC or HbS/β-thalassemia were enrolled from 57 US centers and assessed every 6 mo until 3 y. Differences between pediatric (<18 y) and adult pts at 3 y are reported.Results: Among 498 pts (317 pediatric; 181 adults) completing baseline visit, 74.1% had HbSS, 15.3% HbSC and 10.4% HbS/β-thalassemia; 61 pts discontinued the study. At baseline, pediatric pts had more asthma/airway reactive disease, dactylitis, and splenic sequestration (Table 1). Adults had significantly poorer performance status (P<0.0001) and more avascular necrosis (AVN), gallbladder disease (GBD), leg ulcers, and pulmonary hypertension (PAH). The most common SCD crisis was pain, both in the 5 y prior to study (86.2% of adults, 72.2% of children) and during study (64.1% of adults, 69.4% of children; Table 2). During study, more pediatric pts had respiratory conditions, including acute chest syndrome (ACS). More than half of all pts were hospitalized; key reasons were pain, fever, and ACS. Significantly more pediatric pts were hospitalized due to fever (P<0.0001) and significantly more adult pts were hospitalized for transfusion/chelation (P=0.0336). Absenteeism from school/work was frequent prior to and during study.Conclusions: Patterns of disease and complications differed between children and adults. Adults had more hospitalizations due to transfusions/chelation and more classic chronic conditions (eg, AVN, GBD and PAH). Absenteeism from school/work was common in both groups. Limitations included the observational study design, variation in time from diagnosis, and lack of mandatory data collection.TABLE 1Baseline Characteristics of Pediatric vs Adult Pts with SCD at 3 Y<18 y(n=317)≥18 y(n=181)Age, y, mean±SD8.9±4.4335.2±12.52*Males, %56.847.0†SCD genotype, n (%)HbSS242 (76.3)127 (70.2)HbSC43 (13.6)33 (18.2)HbS/β-thalassemia32 (10.1)20 (11.0)Karnofsky performance status, n (%)100%105 (33.1)26 (14.4)*90%64 (20.2)54 (29.8)*≤80%22 (6.9)63 (34.8)*Medical history, n (%)Aplastic episode31 (9.8)15 (8.3)Asthma/reactive airway disease97 (30.6)29 (16.0)AVN10 (3.2)61 (33.7)CNSAbnormal TCD28 (8.8)7 (3.9)Seizure15 (4.7)13 (7.2)Silent infarct23 (7.3)11 (6.1)Stroke (lifetime)33 (10.4)27 (14.9)Dactylitis75 (23.7)12 (6.6)GBD48 (15.1)80 (44.2)Leg ulcer018 (9.9)PAH3 (0.9)19 (10.5)Splenic sequestration75 (23.7)15 (8.3)*P<0.0001†P<0.05CNS, central nervous system; TCD, transcranial DopplerTABLE 2Clinical Complications and Treatment Patterns in Pediatric vs Adult Pts with SCD at 3 Y<18 y(n=317)≥18 y(n=181)<18 y(n=317)≥18 y(n=181)Clinical ComplicationsPts with SCD crises in 5 y prior to study, n (%)Pain229 (72.2)156 (86.2)Infections (≥1)135 (42.6)62 (34.3)ACS/pneumonia135 (42.6)40 (22.1)Stroke (lifetime)33 (10.4)27 (14.9)Priapism14 (4.4)14 (7.7)Pts with SCD crises in 3 y during study, n (%)Pain220 (69.4)116 (64.1)Infections (≥1)113 (35.6)53 (29.3)ACS/pneumonia62 (19.6)18 (9.9)Stroke9 (2.8)2 (1.1)Priapism8 (2.5)3 (1.7)Pts hospitalized in 3 y during study, n (%)212 (66.9)111 (61.3)Number of hospitalizations in 3 y during study, n CausesµPain13591Fever‡6313 ‡ACS/pneumonia7028Transfusion/chelation1417 *Infections87TreatmentsPts transfused, n (%)During 12 mo prior to study138 (43.5)96 (53.0)*During 3 y on study172 (54.3)93 (51.4)Chelation therapy, n (%)Pts ever chelated prior to study63 (19.9)59 (32.6)†During 3 y on study40 (12.6)19 (10.5)Pts used hydroxyurea, n (%)Prior to study146 (46.1)88 (48.6)During 3 y on study156 (49.2)78 (43.1)Absenteeism from school/workMissed school, n (%)Prior to study (>20 d in last 12 mo)28 (14.7)5 (25.0)During study (>20 d since last visit)4 (2.5)0Missed work, n (%)Prior to study (>20 d in last 12 mo)012 (22.2)During study (>20 d since last visit)04 (9.5)ACS, acute chest syndrome*P<0.05†P<0.01‡P<0.0001µUp to 3 discharge diagnoses may be listed for any hospital admission DisclosuresHeeney:Novartis: Research Funding. Adams-Graves:Novartis Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau. Paley:Novartis Pharma: Employment. Esposito:Novartis Pharma: Employment. McNamara:Novartis Pharmaceuticals Corporation: Employment. Vichinsky:Novartis : Consultancy, Research Funding, Speakers Bureau.

Sickle Cell Disease Proteinuria Is Not Associated With Systolic Blood Pressure, CSSCD-Defined Hypertension, or Family History Of Hypertension In An International Cohort Of SCD Patients

▪ BackgroundThe prevalence of renal disease in sickle cell disease (SCD) is strikingly high and is associated with morbidity and mortality (Becker et al 2010, Powars et al 2005). In SCD children there is initially hyperfiltration with high GFRs followed by increasing proteinuria in the adolescent and adult SCD pts. (Becker at al 2010). Historically, hypertension (HTN) has been associated with Renal Disease in the general population and a few adult sickle cell nephropathy studies. HTN has been associated with Stroke in SCD. In an ongoing multicenter, international Renal SCD Cohort Study, we investigated the association Microalbuminuria and Macroalbuminuria to Patients Blood Pressure (SBP and DBP), Hypertension based on CSSCD Group Age Defined BP for SCD patients >90%tile (Pegelow et al 1997), and Family history (FH) of Hypertension and Renal Disease in a Crossectional (Peds and Adults), International, Multicenter group of SCD patients. Methods272 pediatric and adult SCD (3-59 y/o) patients were recruited at baseline from 6 Centers (USA: Univ of Michigan, Case Medical Center/Rainbow Babies, Albert Einstein-Montefiore Medical Center, Univ of Connecticut; Italy: Univ. of Padova, Univ of Naples; Ghana: Korle-Bu Teaching Hospital). 88%(N=236) were severe SCD (SSorSBeta Zero) and 12%(N=31) were Mild Phenotype (SC or SBetaPlus). 58% were Children (<18y/o) and 42%(>18y/o) adults. FH of HTN and Renal Disease were obtained in 1st and 2nddegree relatives. Clinical history and laboratory studies including Pain crises patterns, SBP, DBP, BMI, CBC, Serum Crt, were collected. We obtained Urine Microalbumin/Crt(UMA) (mg/gm) obtained in 169 patients and categorized patients into 1) No Microalbuminuria(No UMA)<30mg/gm, 2) Microalbuminuria(MicroUMA) 30-299mg/gm and 3) Macroalbuminuria (MacroUMA) and obtained Urine protein/crt gm/gm(UProtCrt) in 101 SCD pts and were categorized 1) No proteinuria(NoUProt) <0.2 and 2) Macroproteinuria(MacroUProt)>0.2. Patient's HTN was defined based on CSSCD SBP or DBP> 90%tile for each specifically defined age group( Pegelow et al 1997). ResultsIn our SCD Renal Cohort Study, NoUMA in 71%(110/169), MicroUMA in 29%(48/169), MacroUMA in 2.2%(6/169) were observed. We also found NoUProt in 75%(N=75) and MacroUProt in 25%(n=25) within our cohort. Severe SCD pts represented 96%(n=46) of the MicroUMA pts, 100% or MacroUMA pts(N=6), and 92% MacroUProt pts(N=23). Proteinuria was disproportionately represented within the Adult SCD pts : 50% of Adults with MicroUMA(n=31) while only 16%(n=17) of Peds. UMA Mean Adult levels was 102(mean) vs. Peds UMA levels of 22(mean),(p=0.009); Also, Adult UProtCrt=0.21(mean)levels were >Peds=0.16, (p<0.001). HTN defined as SBP>90%tile or DBP >90%tile was present in 30%of the subjects(n=77).Thirty-One Percent(n=32) of Adults and 30%(n=45) of Peds pts had HTN. In a Bivariate Analysis(Pearson's Correlation), HTN was not associated with UMA levels(p=0.919) or UPrtCrt levels(p=0.330). Further, mean UMA was lower in HTN SCD pts( m=24) vs NonHTN(SBP) pts(m=51). Mean UProt levels lower in the HTN group(0.15 ) vs NonHTN(0.20). SBP alone was not associated with UMA( p=0.083), UPrt( p=0.804) levels, MicroUMA(p=0.596). While FH of HTN was common in 75% of pts, FH HTN was not associated with UMA and UProtCrt levels, MicroUMA, MacroUMA, MacroUProt( p>0.05) patients. FH of Renal Disease was not associated with Proteinuria within our Cohort. However, Age( p<0.001: UProtCrt levels, UMA levels, MicroUMA, SBP) and hemoglobin(p=0.034: UProt Crt levels) was significantly associated with proteinuria within our cohort based on Bivariate Analysis. BMI was associated with SBP(p<0.001) and DBP(p<0.001) but not UProt or UMA levels. Further analysis revealed increasing proteinuria(UMA) within aging SCD pts:( 6-10 UMA= 15, 11-19 UMA =42, >20y/o UMA=114)(p=.035 One Way Anova) ConclusionsSystolic Blood Pressure, HTN defined as SBP>90%tile or DBP >90%tile from the CSSCD Group, FH of HTN was not associated with Micro or Macroproteinuria based on UProtCrt and UMA levels in an international, cross-sectional cohort of SCD patients. Hemoglobin level and older age were strongly associated with proteinuria within our cohort of patients, consistent with previously well established studies. These findings are supportive of other factors outside of HTN including those intrinsic to SCD contributing to early onset SCD nephropathy. Disclosures:Perrotta:Novartis: Research Funding.

High Resource Utilizers From The Multicenter Compact Study Of Complications In Patients With Sickle Cell Disease and Utilization Of Iron Chelation Therapy

IntroductionWhile treating patients (pts) with sickle cell disease (SCD) can be costly, costs are not evenly distributed across pts; rather, a minority of pts accounts for a majority of costs. Identifying those pts who consume a disproportionately large share of healthcare resources can assist payers and providers in directing appropriate and targeted interventions to deliver better pt care with lower costs. The objective of this study was to understand characteristics of pts who have increased utilization of inpatient (IP) and emergency department (ED) resources in a population of SCD pts ≥16 years old. MethodMedical records of 254 SCD pts ≥16 years old were retrospectively reviewed between 8/2011 and 7/2012 at three US tertiary care centers. The high utilization threshold was derived from the literature and defined as pts with ≥ 5 days of IP+ED care (assuming 1 day/ED visit) for SCD-related complications per year (high utilizer group). Pts were also classified into cohorts based on cumulative blood transfusion units and use iron chelation therapy (ICT): <15 units, no ICT (Cohort 1 [C1]), ≥15 units, no ICT (Cohort 2 [C2]), and ≥15 units, with ICT (Cohort 3 [C3]). SCD complication rates were expressed as the number of SCD complications per pt per year (PPPY); rate ratios (RRs) were used for cohort comparisons. A logistic regression was used to identify risk factors associated with high utilization of IP+ED care. ResultsOf the 254 pts (C1: 69, C2: 91, C3: 94), 30% (n =76) were classified as high utilizers (C1: 14 [18.4%], C2: 37 [48.7%], C3: 25 [32.9%]). Patients in the high utilizer group were younger (median [range] (21 years old [16-65], vs. 23 years old [16-59]) and had shorter follow-up (4.2 years [0.6-23.9], vs. 5.4 years [0.5-33.3]) compared to the rest of the sample. Those in the high utilizer group accounted for 68% of all SCD-related complications and over 88% of all IP+ED days for treatment of these complications. Similar to the rest of the sample, pain (81%) and infection (7%) were the two key complications seen in this high utilizer group. The rate of IP +ED days was significantly higher among the high utilizer group with 16.63 [16.28-16.99] IP+ED days PPPY compared to 0.89 [0.84-0.94] PPPY for other pts. Similarly, the high utilizer group had 4.58 [95% CI: 4.39-4.76] IP+ED visits PPPY, compared to 0.34 [0.31-0.37] visits PPPY for other pts (Table). Among regularly transfused pts (C2+C3) in the high utilizer group, those who received ICT had lower rates of IP+ED visits (C2 vs. C3 rate ratio [RR] [95% CI]: 1.31[1.20-1.44]), IP+ED days (C2 vs. C3 RR: 1.30 [1.24-1.36]), and readmission to IP+ED settings within 30 days (1.70 [1.49-1.93]) compared with those who did not (Table). History of infections (odds ratio: 7.45, p<0.0001) was associated with an increased risk of high utilization of IP+ED care. [Display omitted] ConclusionResults from this study show that a relatively small fraction of SCD pts account for the majority of IP+ED visits. Moreover, among regularly transfused pts identified as high utilizers, those who received ICT had lower rates of IP+ED utilization than those who did not. Pts receiving ICT may also receive closer monitoring, which may help with early identification and intervention to delay or prevent the development of complications and improve outcomes. Closer management of pts with SCD, especially those at risk of becoming high utilizers, is critical to lowering IP+ED utilization and reducing the overall costs of care. Disclosures:Jordan:Novartis Pharmaceuticals Corporation: Consultancy. Adams-Graves:Analysis Group, Inc.: Research Funding. Kanter-Washko:Analysis Group, Inc.: Research Funding. Oneal:Novartis Pharmaceuticals Corporation: Honoraria; Analysis Group, Inc.: Research Funding. Sasane:Novartis Pharmaceuticals: Employment. Vekeman:Novartis Pharmaceuticals: Research Funding. Bieri:Novartis Pharmaceuticals Corporation: Research Funding. Marcellari:Novartis Pharmaceuticals Corporation: Employment. Magestro:Novartis Pharmaceuticals: Employment. Adams:Novartis Pharmaceuticals Corporation: Research Funding. Duh:Novartis Pharmaceuticals: Research Funding.

Age-Related Emergency Department Reliance and Healthcare Resource Utilization in Patients with Sickle Cell Disease

AbstractAbstract ▪475▪This icon denotes a clinically relevant abstract Introduction:For sickle cell disease (SCD) patients (pts), inadequate care during pediatric to adult transition may result in increased emergency department (ED) utilization. Emergency department reliance (EDR: total ED visits/total ambulatory [outpatient + ED] visits) identifies the proportion of ED visits in relation to all ambulatory visits and differentiates between acute episodic ED users from those who may not have adequate access to outpatient care. The aim of this study is to investigate age-related patterns of EDR and associated healthcare costs in pediatric SCD pts and those transitioning from pediatric to adult care. Methods:State Medicaid data from FL (1998–2009), NJ (1996–2009), MO (1997–2010), IA (1998–2010), and KS (2001–2009) were used for this study. Pts with ≥2 SCD diagnoses (ICD-9 282.6x) and ≥1 blood transfusion were included in the analysis. Pts were followed for as long as they were enrolled in Medicaid. Quarterly rates of outpatient visits, ED visits, EDR, SCD complications associated with ED visits, and ED visits resulting in hospitalization were evaluated. Total healthcare costs were calculated and stratified by outpatient (OP), inpatient (IP), ED, and prescription drug (Rx). SCD complications included pain, stroke, leg ulcers, avascular necrosis, infections, as well as pulmonary, renal, and cardiovascular events. Based on published thresholds, high EDR was defined as >0.33. A logistic regression model was used to assess associations between high EDR and transition age (<18 vs. ≥18 years [yrs]), transfusions, hydroxyurea use, and SCD complications. Other covariates included transfusions during the previous quarter, other relevant medications (e.g.: pain medication, diuretics, anticoagulants), comorbidities (e.g.: hypertension, myocardial infarction, liver disease), and, serving as proxies for overall health status, the frequency of OP, IP, and ED visits during the previous quarter. Regressions analyses were also used to calculate adjusted costs differences between pts with high vs. low EDR. Findings:A total of 3,208 pts were included (FL: 1,550, NJ: 992, MO: 489, KS: 121, IA: 56) in the study. Each pt was observed for an average (SD) of 6.0 (3.1) yrs. Average ED visits/quarter increased from 0.76 to 2.29 between age 15 and 24, reaching a peak of 2.9 at age 36 (Figure 1). Regardless of age, the most common SCD complications associated with ED visits were pain, infection, and pneumonia. Beginning at age 15, EDR rose from 0.17 to reach 0.29 at age 22, and remained high throughout adulthood. The quarterly rate of ED visits resulting in hospitalizations followed a similar pattern. Regression analysis indicated that pts were more likely to have high EDR during the post-transition period (≥18 yrs old, odds ratio [OR]: 2.38, p<0.001) and when experiencing an SCD complication (OR: 4.18, p<0.001). Pts with high EDR incurred statistically significantly higher inpatient and ED costs, resulting in significantly higher total costs (high vs. low EDR, unadjusted costs difference, OP: -$441, p<.001; IP: $7,427, p<.001; ED: $442, p<.001; Rx: -$447, p=0.182; total: $7,376, p<.001 [Table 1]; adjusted costs difference, OP: -$285; IP: $3,485; ED: $120; Rx: -$91; total: $3,086, p<.001 for all). Conclusion:Compared to children, pts transitioning to adulthood relied more on ED for their care. Moreover, pts with high EDR incurred more frequent hospitalizations and significantly higher healthcare costs, highlighting the need to improve transition related support including better access to primary care and increased engagement with SCD patients. [Display omitted] Table 1Mean Quarterly Healthcare Costs in Patients with High vs. Low EDRLow EDR (≤ 0.33) [A]High EDR (> 0.33) [B]Cost Difference [B] - [A]P-valueTotal Costs ($)7,33914,7157,376<.001Before 18 yrs old5,9839,6153,633<.001After 18 yrs old9,11817,2388,121<.001OP Services ($)1,222781−441<.001Before 18 yrs old1,207510−697<.001After 18 yrs old1,243915−328<.001IP Services ($)3,54310,9717,427<.001Before 18 yrs old2,5547,3524,798<.001After 18 yrs old4,84112,7627,920<.001ED Costs ($)57499442<.001Before 18 yrs old35191157<.001After 18 yrs old85651566<.001Rx costs ($)1,262816−4470.182Before 18 yrs old981330−651<.001After 18 yrs old1,6321,056−576<.001 Disclosures:Blinder:Novartis Pharmaceuticals: Consultancy, Research Funding. Vekeman:Novartis Pharmaceuticals: Research Funding. Sasane:Novartis Pharmaceuticals: Employment. Trahey:Novartis Pharmaceuticals: Research Funding. Paley:Novartis Pharmaceuticals: Employment. Magestro:Novartis Pharmaceuticals: Employment. Duh:Novartis Pharmaceuticals: Research Funding.

Age-Related Iron Chelation Utilization and Healthcare Costs in Patients with Sickle Cell Disease (SCD)

Abstract 338 Background:For patients (pts) with SCD receiving regular blood transfusions (tf), iron chelation therapy (ICT) alleviates complications associated with iron overload. Pediatric pts tend to receive comprehensive care, including blood tf to avoid SCD-related complication and, as necessary, ICT. However, as pts transition to adult care, follow up is less constant and discrepancies are seen in care management. The aim of this study is to evaluate tf patterns, utilization of ICT among chronically transfused pts, and healthcare costs in pediatric and adult pts with a focus on the transitioning period from pediatric to adult care. Methods:State Medicaid data from the FL (1998–2009), NJ (1996–2009), MO (1997–2010), IA (1998–2010), and KS (2001–2009) were used for this study. Pts with ≥2 SCD diagnoses (ICD-9 282.6x) and ≥1 tf following the 2nd SCD diagnosis were included. Pts were followed for as long as they were enrolled in Medicaid. Pts were considered chronically transfused from the time of their 8th tf. Each tf event was defined as a unique day when ≥1 procedure code for packed RBCs, whole blood, or exchange tf was recorded. Quarterly rate of tf was calculated among all SCD pts and proportion of pts receiving ICT was calculated among pts who received ≥8 tf. Quarterly healthcare costs, stratified by outpatient (OP) and inpatient (IP) services and prescription drug (Rx) costs were calculated. Regression analyses were conducted to identify the main drivers of healthcare costs among pts with ≥8 tf. Covariates included, among others, transition age (<18 vs ≥18 yrs), SCD complications (pain, infection, stroke, cardiomyopathy, renal disease, and Moyamoya disease), current and previous tf, prescription of hydroxyurea, relevant comorbidities, and resources utilization. Results:3,208 pts were included (FL: 1,550, NJ: 992, MO: 489, KS: 121, IA: 56) in the study. Each pt was observed for an average (SD) of 6.0 (3.1) yrs. 917 pts received ≥8 tf during their observation period. The proportion of pts with ≥8 tf increased from 4% at 2 yrs of age to approximately 24% at 16 yrs old (Fig 1). The proportion of pts with ≥8 tf remained relatively stable around 20% thereafter, in contrast with the overall rate of tf which decreased after age 16. The proportion of chelated pts increased from 4% at 2 yrs of age to a maximum of 50% at age 13 (Fig 1). The proportion of chelated pts then decreased steadily during the following 10 yrs to reach 10% at age 23 and oscillated around that level thereafter. Healthcare costs increased from ages 5 to 19 for all SCD pts ($3,907 to $10,317 per pt-quarter) and those with ≥8 tf ($4,500 to $15,078 per pt-quarter), and remained high through adulthood. Pts with ≥8 tf had greater healthcare costs than the overall SCD population at all ages. Despite the higher Rx costs, pts receiving ICT incurred statistically significantly lower IP costs than chronically transfused pts receiving no ICT, resulting in no statistically significant cost difference (unadjusted cost difference, Rx: $2,285, p<.001; OP: $851, p=.156; IP: -$2,584, p<.001; total: $552, p=.493 [Table 1]; adjusted cost difference, Rx: $2,746, p<.001; OP: -$813, p=.036; IP: -$936, p<.001; total: $61, p=.098). Regression analyses also revealed that SCD complications was the main driver of healthcare costs among pts with ≥8 tf (incremental cost increase: $3,955; p<.001). [Display omitted] Table 1Mean Quarterly Healthcare Costs in Chronically Transfused Pts (≥8 tf) With vs. Without ICTNo ICT (N = 663) [A]ICT (N = 450) [B]Cost Difference [B] - [A]P-valueTotal Costs ($)11,66712,219552.493Before 18 yrs old6,80011,3524,552<.001After 18 yrs old14,03913,263−776.559IP Services ($)4,5661,982−2,584<.001Before 18 yrs old1,9241,006−918.013After 18 yrs old5,8533,157−2,696<.001OP Services ($)6,0576,908851.156Before 18 yrs old4,5336,7762,243<.001After 18 yrs old6,8007,068268.789Rx Costs ($)1,0443,3292,285<.001Before 18 yrs old3433,5703,227<.001After 18 yrs old1,3863,0391,653<.001 Conclusions:Pts transitioning to adult care received less tf and ICT when chronically transfused, and had higher healthcare costs than pediatric pts. While other age-related factors are likely to impact SCD treatment patterns and healthcare resource utilization, the marked decrease in tf and proportion of chelated pts and increase in healthcare costs during the transition from pediatric to adult care suggest that tf and ICT are markers for lower healthcare costs in SCD patients. Disclosures:Blinder:Novartis: Honoraria. Vekeman:Analysis Group: Analysis Group has received research grant from Novartis pharmeceuticals, Employment. Trahey:Analysis Group: Analysis group received research grant from Novartis Pharmaceuticals, Employment. Sasane:Novartis Pharmaceuticals: Employment. Paley:Novartis Pharmaceuticals: Employment. Duh:Analysis Group: Analysis group received research grant from Novartis Pharmaceuticals, Employment.