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Incremental improvement in care for children with sickle cell disease (SCD), arising from government-funded research over the last 4 decades, resulted in a dramatically reduced childhood mortality. However, the impact of iterative research and disease modifying therapy (DMT) on adults with SCD has not been as strong. Until now, there has been no coordinated, longitudinal, generalizable, natural history study of SCD that allowed for an assessment of the contemporary adult population. Here, we describe demographics at enrollment and cross-sectional clinical characteristics of 570 adults with SCD (SCA, homozygous HbSS or HbSb0 N=387, 68%, and compound heterozygous SCD variant, HbSC or HbSb+ N=183, 32%, Table I) on whom we have evaluable data. These data are from the multi-site REDCap-based prospective Globin Research Network for Data and Discovery (GRNDaD) registry, comprising 11 centers with over 1100 consented adults and children. The objective of this work was to evaluate the cohort at year of entry, including the use and clinical associations with DMT, and to explore indicators of disease progression as patients age. 16% of adults with SCA and 9.6% with variant disease stroke; 60.9% of adults with SCA and 41% with variant disease had a history of acute chest syndrome. Albuminuria was prevalent in both SCA (39.5%) and variant disease (19.4%). 185 adults (185/387, 47.8%) with SCA, previously referred for symptoms in clinic, had recorded tricuspid regurgitant jet velocity measurements, with a significantly abnormal result (>2.7 m/s), in 92 (92/185, 49.7%). At enrollment, 45% of adults with SCA (175/387) and 14% of adults with variant disease (25/183) were on hydroxyurea (HU); 20.4% of adults with SCA were on chronic transfusions (79/387) compared with 7% of adults with variant disease (13/183). One third of all adults with SCA were not on or were not consistently on DMT, and had laboratory evidence for increased hemolysis (Table 1). Adults with SCA who were on HU had a higher MCV and higher HbF than other treatment states (Table 1). However, only 34% (60/175) of adults with SCA on HU were at maximally tolerated dose (MTD), per guideline-based recommendations, i.e. ANC ≤4.0 x109/L. On HU, those in the lowest quartile for ANC (5.7 x109/L, N=34), but did not otherwise differ (including mean HbF, which was not measured in a standardized way). In older adults with SCD (Table 2), fewer people with SCA than with variant disease were >54 years old, (26/387 HbSS, 7%, vs. 34/183, 19%, respectively). The older adult with SCA had a depressed reticulocyte count and a trend towards a higher creatinine. 45% of adults with SCA were on HU, and only a minority were at MTD, highlighting the challenges to optimal long-term therapy in chronic illness. Those patients not stably on DMT had laboratory evidence for worse anemia and hemolysis, without an evident increase in hospital admissions, perhaps due to a hyper hemolytic phenotype. Despite a more intensive regimen, SCA patients on transfusions had a higher Hgb but did not have hemolysis labs that differed from SCA patients on HU. Further, there was no difference in hospitalizations amongst treatments for SCA, although a decrease in hospitalizations was detectable in variant disease (Table 1). Successful use of DMTs in SCA was challenging even in academic centers, and there was evidence for ongoing hemolysis in treated and untreated patients. These real world data provide useful information about adults (>17 years) with SCD. These data highlight opportunities to improve adherence to therapy (patient-centered) and to prescribing guidelines (provider-centered), and to consider less-burdensome alternatives. Importantly, we found that a large proportion of people with SCA were not on DMT, and with HU often not at MTD. In future, the GRNDaD registry will enable prospective longitudinal real-world analyses of the impact of DMTs and/or newer therapies on clinical outcomes, will enhance quality improvement, and will allow us to more fully explore clinical characteristics, of SCA and variant disease, in the aging adult. Disclosures Puri-Sharma: Bluebird Bio: Current Employment. Chawla:Bluebird Bio: Current Employment. Field:Shires: Research Funding; Ironwood: Research Funding. Neumayr:Emmaus: Consultancy; Bayer: Consultancy; CTD Holdings: Consultancy; Pfizer: Consultancy; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Micelle: Other: Site principal investigator; GBT: Other: Site principal investigator; PCORI: Other: site principal investigator; Novartis: Other: co-investigator; Bluebird Bio: Other: co-investigator; Sangamo Therapeutics: Other; Silarus: Other; Celgene: Other; La Jolla Pharmaceuticals: Other; Forma: Other; Imara: Other; National Heart, Lung, and Blood Institute: Other; Health Resources and Services Administration: Other; Centers for Disease Control and Prevention: Other; Seattle Children's Research: Other. Desai:Pfizer, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; GBT, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ironwood Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Rockpointe Continuing Medical Education Company: Consultancy. Lanzkron:GBT: Research Funding; HRSA: Research Funding; Ironwood: Research Funding; NHLBI: Research Funding; PCORI: Research Funding; Pfizer: Research Funding; Pharmacy Times Continuing Education: Honoraria; Prolong: Research Funding. Little:Hemex Health, Inc.: Patents & Royalties: Microfluidic electropheresis (patent, no royalties); BioChip Labs: Patents & Royalties: SCD Biochip (patent, no royalties); GBT: Research Funding; GBT: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Research Funding; NHLBI: Research Funding.

Background: Sickle cell disease (SCD) is a genetic disorder that causes significant medical and neurologic morbidity in children. Hydroxyurea (HU) is the primary medication used to prevent these complications. National Heart, Lung, and Blood Institute (NHLBI) guidelines recommend offering HU to children as young as 9 months of age with SCD (HbSS or HbSB0 thalassemia) using a shared decision-making approach. Although HU has proven efficacious it remains underutilized and caregivers report that they are not always actively involved in the decision to initiate this therapy. Reasons for limited HU uptake likely include lack of clinician knowledge and training and negative caregiver perceptions. Thus, we developed the Engage-HU trial as a novel approach to address HU utilization barriers. A critical consideration for this trial was that SCD primarily affects individuals of African and Hispanic/Latino descent. In these minority populations, intervention trials are sometimes terminated early because of recruitment difficulties related to mistrust of research, caregiver burden, and transportation issues. As such, the Engage-HU trial design included best-practice strategies for recruiting people of color in research. This study describes these strategies, the initial recruitment plan, preliminary recruitment outcomes and strategies, and our procedural adaptations. Study Design and Methods: Engage-HU is a randomized control trial (NCT03442114) to assess how clinicians can engage caregivers in a shared discussion that considers their values and preferences and includes evidence that supports HU. Engage-HU compares two dissemination methods for clinicians to facilitate shared decision-making with caregivers of young children with SCD: 1) the American Society of Hematology Pocket Guide, and 2) the HU Shared-Decision Making (H-SDM) Toolkit. The study aims to recruit 174 caregivers and evaluate the effectiveness of the dissemination methods on patient-centered outcomes (caregiver confidence in decision-making and perceptions of experiencing shared decision-making) as well as HU uptake and child health outcomes. Eligible children are aged 0 to 5 years, candidates for HU, and their caregiver has not made a decision about HU in the past 3 months. The trial is being conducted at 9 sites in the United States and uses a stepped-wedge design. Data will be analyzed based on the intent-to-treat principle. All participants will remain in the arm of the study to which they were randomized, regardless of whether or not they receive the assigned dissemination method. The primary endpoints are caregiver decisional uncertainty and caregiver perception of shared decision-making measured using validated tools. Data will be analyzed using a linear mixed effects regression model with a robust variance estimator and maximum likelihood estimation with observations clustered within site. The Engage-HU trial includes adaptations to increase recruitment such as tailored messaging, a relational recruitment approach, streamlined data collection, and a Stakeholder Advisory Committee. However, even with these adaptations, the first 6-months of the trial yielded lower than anticipated recruitment. Rather than terminate the trial or accept low enrollment, the research team implemented a series of recruitment strategies to address barriers including helping to improve research coordinator knowledge of the study purpose and adjusting no-show and follow-up procedures (e.g., calls to families after missed appointments and reminder calls before appointments). Site clinicians and clinic staff were provided with additional training so they could give more context about Engage-HU to caregivers and the study principal investigator led monthly "all coordinator" calls to provide support by sharing updates and experiences about successful recruitment. Implementation of these strategies resulted in triple the number of enrollments over the next 7-months compared to the previous 6-months (Table 1). Our goal in sharing this information is to provide lessons learned that can be implemented in future trials with the systematically underserved SCD population. It is also anticipated that methods described here may also inform clinical approaches to better engage caregivers of young children around critical clinical conversations, such as initiating medications like HU. Disclosures King: Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bioline: Consultancy; RiverVest: Consultancy; Novimmune: Research Funding; Celgene: Consultancy; Tioma Therapuetics: Consultancy; Amphivena Therapeutics: Research Funding; WUGEN: Current equity holder in private company; Cell Works: Consultancy; Incyte: Consultancy. Smith-Whitley:Prime: Other: Education material; Celgene: 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; Novartis: Membership on an entity's Board of Directors or advisory committees. Neumayr:Emmaus: Consultancy; Bayer: Consultancy; CTD Holdings: Consultancy; Pfizer: Consultancy; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Micelle: Other: Site principal investigator; GBT: Other: Site principal investigator; PCORI: Other: site principal investigator; Novartis: Other: co-investigator; Bluebird Bio: Other: co-investigator; Sangamo Therapeutics: Other; Silarus: Other; Celgene: Other; La Jolla Pharmaceuticals: Other; Forma: Other; Imara: Other; National Heart, Lung, and Blood Institute: Other; Health Resources and Services Administration: Other; Centers for Disease Control and Prevention: Other; Seattle Children's Research: Other. Yates:Novartis: Research Funding. Thompson:Novartis: Consultancy, Honoraria, Research Funding; CRISPR/Vertex: Research Funding; BMS: Consultancy, Research Funding; Baxalta: Research Funding; Biomarin: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding.

Introduction: Heme, an iron-containing protoporphyrin, is an essential component of hemoglobin that binds oxygen for delivery to tissues. In sickle cell disease, intravascular hemolysis leads to the presence of cell-free hemoglobin and heme, which may contribute to oxidative damage and activation of inflammatory pathways. Hemoproteins such as haptoglobin and hemopexin provide pathways to remove hemoglobin and heme, respectively, from circulation. Due to its hydrophobic nature, heme also intercalates in cell membranes and binds to plasma components such as albumin and lipoproteins, though with varying affinity. Hemopexin has high affinity for heme and removes heme from other heme pools in blood to counter the highly toxic properties of heme unbound to hemoproteins. Due to chronic hemolysis, hemopexin is depleted in individuals with sickle cell disease. We hypothesize that the reduction in heme binding capacity leads to increased unbound heme in blood and contributes to the pathogenesis of sickle cell disease. To define the different heme binding pools in patients with sickle cell disease, we developed a method requiring small amounts of plasma which allows measurement of total and hemoprotein-unbound heme. With this method, we can quantify the binding capacity of plasma for heme and correlate that with measurement of heme scavenging proteins. Methods: Blood from healthy individuals and sickle cell patients was collected in EDTA as anticoagulant under IRB approval. Plasma was separated by centrifugation from whole blood, and either processed fresh or after freezing at -80°C. Plasma protein was precipitated with a 4-fold volume of acetone at neutral pH (NA) or acidic pH (AA). Under acidic condition, heme is released from all heme binding pools, including hemoglobin, and provides detection of the total heme present in plasma. Under neutral pH condition, only heme unbound to plasma proteins is extracted. Once extracted, samples were dried and resuspended in DMSO. Heme concentration was spectrophotometrically determined at 400nm using standard curves prepared from hemin added in AA or NA. To determine heme binding capacity, hemin was added to serial dilutions of plasma and extracted in NA and AA as above. The appearance of heme in NA relative to AA represents the point at which heme binding capacity of plasma was saturated. This was compared to measurement of hemopexin and haptoglobin using commercially available ELISA measurements. Hemopexin and albumin were added to samples to modulate heme binding capacity. Results: Heme concentration closely correlates with spectroscopic measurement of heme in DMSO confirming reliable quantification of total and unbound heme in acidic and neutral acetone extractions as low as 2.5µM. We next show that heme binding capacity can be determined. Heme added to plasma was effectively recovered in AA extracts and begins to appear in the NA extract when binding sites start to become saturated. We note that not all sites appear to be fully saturated before heme is detected in NA extract. Addition of hemopexin to plasma increased the binding capacity on an equimolar basis, indicating that hemopexin effectively binds heme present in plasma. In samples from patients with sickle cell disease, concentration of total and unbound heme varied widely, and did not necessarily correlate with degree of intravascular hemolysis, estimated based on the measurement of cell free hemoglobin. Both the capacity of plasma to bind heme and levels of hemopexin indicated that, in a number of patients, the amount of heme present was greater than the ability of hemopexin to bind cell free heme. Discussion: We present a novel method to quantitatively differentiate hemoprotein-bound and unbound heme in plasma, the latter of which is pathologically relevant in sickle cell disease. Our data show significant variation in the concentration of total and unbound heme in sickle cell patient samples, and that the binding capacity in sickle cell plasma only partially correlates to the degree of hemolysis measured based on cell free hemoglobin. Patients are currently enrolled in a clinical study to measure intra-patient differences in heme and heme-binding capacity during steady state and during acute sickle cell-related illness. Understanding the clinical implications of heme and heme scavengers may provide insights into diagnostic and therapeutic targets for patients with sickle cell disease. Disclosures Neumayr: Emmaus: Consultancy; Bayer: Consultancy; CTD Holdings: Consultancy; Pfizer: Consultancy; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Micelle: Other: Site principal investigator; GBT: Other: Site principal investigator; PCORI: Other: site principal investigator; Novartis: Other: co-investigator; Bluebird Bio: Other: co-investigator; Sangamo Therapeutics: Other; Silarus: Other; Celgene: Other; La Jolla Pharmaceuticals: Other; Forma: Other; Centers for Disease Control and Prevention: Other; Seattle Children's Research: Other; Imara: Other; National Heart, Lung, and Blood Institute: Other; Health Resources and Services Administration: Other. Vichinsky:Bluebird Bio: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Agios Pharmaceuticals: Consultancy, Research Funding; GBT: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Kuypers:Forma Therapeutics, Inc.: Research Funding.

Background: The FDA approved hydroxyurea (HU) for the treatment of sickle cell disease (SCD) in children because it was deemed a safe and efficacious treatment. HU modifies the course of the disease, reduces complications, improves survival, and has few long-term side effects. Despite these benefits, HU uptake remains low for young children. Over 75% of patients who could benefit from HU do not receive the treatment. NHLBI clinical practice guidelines recommend use of shared decision making for HU initiation but currently, there is no "gold standard" for hematology providers to follow when beginning their discussion about HU. Thus, there is likely a gap between care guidelines and clinical practice. A first step in closing this gap is to better understand the current practice utilized by hematology providers when discussing HU as a therapeutic option. Objectives: The goal of the present study is to describe current practice used by hematology providers when discussing HU with parents of young children with SCD (0 - 5 years of age), Our primary aims are: 1) Map the process of offering HU to identify common themes, overlaps, and variations, 2) Examine the impact of a brief video presentation about the NHLBI HU guidelines on provider knowledge and comfort levels. Methods: The dissemination of methods to increase adherence to NHLBI HU guidelines are being evaluated as part of a clinical trial (NCT03442114). Hematology providers at 6 children's hospitals serving young patients with SCD completed process maps that described their current practice for discussing HU initiation with parents. Twenty five hematology providers at 10 institutions across the United States viewed a video didactic presentation on the NHLBI HU guidelines for SCD. Knowledge and comfort regarding discussing HU was assessed using a 10-point scale before and after the video. We also collected data on provider demographics, years practicing, and percentage of patients seen with SCD each week in their practice. Results: Preliminary analyses identified common themes (see Table 1 for provider characteristics). All 6 sites reported that labs and vitals were taken prior to the visit so they could be reviewed with the family. A medical doctor, nurse practitioner, or licensed practical nurse (LPN) led the HU initiation discussion. The majority of sites give their families HU-related materials to take home after the discussion and followed-up regarding the family's decision at the next clinic visit (i.e. planned for a two-visit HU initiation process). Variations identified included providing HU-related materials to the family prior to the visit, when the discussion would occur, and whether NHLBI HU guidelines framed the discussion (Figure 1). Paired samples t-tests assessed for change in medical provider reported HU knowledge and comfort before and after the SCD didactic presentation. Data revealed that there were no differences in provider comfort,t(21) = .77, p = .45, d = .03. In contrast, there was a trend towards a significant increase in medical provider knowledge from before (M = 8.4, SD = 2.3) to after (M = 8.7, SD = 2.1) the presentation, t(21) = 1.8, p = .08, d = .11, small effect. Correlation analyses determined that higher baseline provider knowledge and comfort with HU were significantly correlated with seeing more SCD patients on a weekly basis (Figure 2). Discussion: This study identified common elements of clinical practice for HU initiation in young children with SCD, but variations were also revealed. All institutions in the study obtained lab work prior to the discussion with the family; however the provider initiating the discussion varied by site (e.g., 1 site used an LPN). Most institutions plan for a two-visit discussion as families may not be ready to make a decision during the first visit but feel more supported over time. It is critical that patients and families make their decision based on SCD-specific HU information. Study data indicated that a brief didactic presentation elicited a small improvement provider HU knowledge. Moreover, exposure to the SCD population was strongly related to knowledge and comfort with HU, suggesting that hematology providers with more experience working with patients with SCD may be in the best position to initiate discussions about HU. The incorporation of decision support tools might help to support hematology providers and reduce the variation across institutions observed in our study. Disclosures King: Tioma Therapeutics (formerly Vasculox, Inc.):: Consultancy; RiverVest: Consultancy; Novimmune: Research Funding; WUGEN: Equity Ownership; Celgene: Consultancy; Cell Works: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Incyte: Consultancy. Piccone:Hemex Health, Inc.: Patents & Royalties. Neumayr:Terumo: Research Funding; Apopharma: Consultancy; PCORI: Research Funding; NHLBI: Research Funding; Bluebird Bio: Research Funding; Sancillo: Research Funding; Seattle Children's Research Grants: Research Funding; Doris Duke Foundation: Research Funding; Novartis: Research Funding; Bayer: Consultancy; Celgene: Research Funding; Imara: Research Funding; Sangamo: Research Funding; Silarus: Research Funding; Pfizer: Consultancy, Research Funding; Emmaus: Consultancy; CTD Holdings: Consultancy; GBT: Research Funding; La Jolla Pharmaceuticals: Research Funding; HRSA: Research Funding; CDC: Research Funding. Meier:CVS Caremark: Consultancy.

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

Background Transfusions are the primary therapy for thalassemia but have significant cumulative risks. In 2004, the Centers for Disease Control and Prevention (CDC) established a national blood safety monitoring program for thalassemia. This report summarizes the population and their previous nonimmune and immune transfusion complications. Study Design and Methods The CDC Thalassemia Blood Safety Network is a consortium of centers longitudinally following patients. Enrollment occurred from 2004 through 2012. Demographics, transfusion history, infectious exposures, and transfusion and nontransfusion complications were summarized. Logistic regression analyses of factors associated with allo- and autoimmunization were employed. Results The race/ethnicity of these 407 thalassemia patients was predominantly Asian or Caucasian. The mean ± SD age was 22.3 ± 13.2 years and patients had received a mean ± SD total number of 149 ± 103.4 units of red blood cells (RBCs). Multiorgan dysfunction was common despite chelation. Twenty-four percent of transfused patients had previous exposure to possible transfusion-associated pathogens including one case of babesia. As 27% were immigrants, the infection source cannot be unequivocally linked to transfusion. Transfusion reactions occurred in 48%, including allergic, febrile, and hemolytic; 19% were alloimmunized. Common antigens were E, Kell, and C. Years of transfusion was the strongest predictor of alloimmunization. Autoantibodies occurred in 6.5% and were associated with alloimmunization (p

Iron overload is the primary cause of mortality and morbidity in thalassemia major despite advances in chelation therapy. We performed a pilot clinical trial to evaluate the safety and efficacy of combined therapy with deferasirox (DFX, 20-30 mg/kg daily) and deferoxamine (DFO, 35-50 mg/kg on 3-7 days/week) in 22 patients with persistent iron overload or organ damage. In the 18 subjects completing 12 months of therapy, median liver iron concentration decreased by 31% from 17.4 mg/g (range 3.9-38.2 mg/g) to 12.0 mg/g (range 0.96-26.7 mg/g, P

Background: Neurodegeneration with Brain Iron Accumulation (NBIA) is a group of rare genetic disorders characterized by progressive degenerative motor symptoms and the accumulation of iron in the basal ganglia. Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a form of NBIA caused by a mutation in the PANK2 gene leading to a deficiency in pantothenate kinase. Phospholipase A2G6-Associated Neurodegeneration (PLAN) is caused by a mutation in the PLA2G6 gene resulting in impaired phospholipase activity. Current understanding of systemic changes in NBIA disorders is limited, leaving no clear diagnostic biomarkers. Monitoring the systemic changes could identify candidate biomarkers for assessing disease severity and evaluating the efficacy of new therapies. Previous studies of Parkinson's disease (PD) have found a systemic burden of increased oxidative stress and chronic inflammation accompanies the neurological symptoms of the disease. Similarly, abnormal systemic iron regulation associated with brain iron accumulation as well as damage associated with neuromuscular degeneration could lead to increased oxidative stress and a state of chronic inflammation in NBIA. Our initial investigation of a patient with PLAN1, revealed elevated levels of systemic oxidative stress. We investigated a group of PKAN patients as well as continued our investigation of a patient with PLAN to evaluate the possibility of abnormal iron trafficking, increased oxidative stress and chronic inflammation in NBIA. Our aim was to expand our investigation of circulating levels of inflammatory cytokines, oxidative stress markers and iron regulatory and metabolic proteins in NBIA patients to include a group of patients with PKAN. Methods: Plasma samples from 15 PKAN patients were collected at the UCSF Benioff Children's Hospital in Oakland, California. Similarly, a plasma sample from a patient with PLAN was collected in Campbell River, British Columbia. Plasma samples from a matched group of 15 healthy controls were also collected at the University of Victoria. All patients provided informed consent to the study. The pro-inflammatory cytokines IL-6 and TNFα as well as the anti-inflammatory cytokine IL-10 were measured by ELISA. Total levels of the lipid peroxidation product malondialdehyde (MDA) were measured using N-Methyl-Phenyl-Indole (NMPI). Free, acutely generated, MDA not bound to proteins, was measured by removing plasma proteins via a 10KD spin filtration then measuring the MDA content of resulting filtrate using NMPI. Results: The levels of MDA and Free MDA were significantly elevated in PKAN patients at baseline in comparison to controls (p = 0.05, p = 0.03). IL-6 and TNFα were slightly, but not significantly elevated at baseline compared to controls. We previously demonstrated, similar elevations of oxidative stress in our case study of an NBIA patient with PLAN1. Additionally, all three inflammatory cytokines measured for this study expansion in PLAN were higher than average levels observed in the PKAN and control groups (S ee Table 1). Further analysis of systemic biomarkers in NBIA including proteomic analysis of 30 systemic blood proteins, including iron trafficking proteins is ongoing. Conclusions: We expand previous findings of elevated levels of systemic oxidative stress in other neurodegenerative diseases such as PD to include NBIA patients with PKAN and PLAN. We provide novel evidence of elevated levels of Free MDA; representative of an acute oxidative stress burden in NBIA in addition to the previously noted elevation in total MDA levels. We provide preliminary signs that of an accompanying inflammatory burden in NBIA, but a larger sample group may be needed to determine its significance. References M. Minkley, A. Jackson, D. Smith, C. Borchers, E. Vichinsky, R. Nashmi, P.B. Walter and P. M. Macloed. (2017). Neurodegeneration with Brain Iron Accumulation: PLA2G6-Associated Dystonia-Parkinsonism: Clinical and Animal Studies. Presented at the 2017 European Human Genetics Conference, Copenhagen, Denmark . Disclosures Minkley: Apopharma: Research Funding. Neumayr: Apopharma: Research Funding. Walter: Apopharma: Research Funding.

In transfusional iron overload, extra-hepatic iron distribution differs, depending on the underlying condition. Relative mechanisms of plasma non-transferrin bound iron (NTBI) generation may account for these differences. Markers of iron metabolism (plasma NTBI, labile iron, hepcidin, transferrin, monocyte SLC40A1 [ferroportin]), erythropoiesis (growth differentiation factor 15, soluble transferrin receptor) and tissue hypoxia (erythropoietin) were compared in patients with Thalassaemia Major (TM), Sickle Cell Disease and Diamond-Blackfan Anaemia (DBA), with matched transfusion histories. The most striking differences between these conditions were relationships of NTBI to erythropoietic markers, leading us to propose three mechanisms of NTBI generation: iron overload (all), ineffective erythropoiesis (predominantly TM) and low transferrin-iron utilization (DBA).

Chronic transfusion therapy is being used more frequently to prevent and treat the complications of sickle cell disease. Previous studies have shown that the iron overload that results from such therapy in other patient populations is associated with significant morbidity and mortality. In this study we examined the extent of iron overload as well as the presence of liver injury and the predictive value of ferritin in estimating iron overload in children with sickle cell disease who receive chronic red blood cell transfusions. A poor correlation was observed between serum ferritin and the quantitative iron on liver biopsy (mean 13.68 ± 6.64 mg/g dry weight;R = 0.350, P = .142). Quantitative iron was highly correlated with the months of transfusion (R = 0.795, P

There is a significant risk of severe graft-versus-host disease (GVHD) and graft failure after unrelated umbilical cord blood transplantation (CBT) if donor–recipient pairs are mismatched at major histocompatibility complex (MHC) loci. To mitigate these risks after MHC-mismatched CBT, we infused psoralen-treated, photochemically inactivated, mature donor T-lymphocytes with MHC (H2-haplotype) mismatched murine donor fetal near-term peripheral blood (FNPB) cells after sublethal irradiation. We analyzed the rates of donor engraftment, GVHD and long-term survival in H2 haplotype disparate (C57BL/6 [H-2b/Thy1.1] → AKR [H-2k/Thy1.2]) recipient mice. We observed inconsistent donor engraftment after transplantation with cord blood alone, but superior engraftment and long-term survival after FNPB transplantation supplemented with psoralen-treated donor T-lymphocytes. Additionally, there was fatal GVHD after FNPB co-infusion with untreated donor T-lymphocytes, but minimal GVHD after FNPB supplemented with psoralen-treated donor T-lymphocytes transplantation. Donor MHChigh/c-Kit+/lineage−/CD34− stem cells were noted in the recipient bone marrow compartment following co-infusion of photochemically inactivated T-cells with FNPB. Despite the non-myeloablative preparation before FNPB infusion, complete hematological recovery was delayed until 50–60 d after transplantation. We observed that co-transplantation of psoralen-treated donor T-lymphocytes with FNPB facilitated durable engraftment of donor hematopoietic stem cells in the marrow and splenic compartments with complete but delayed recovery of all hematopoietic lineages. This CBT model establishes the possibility of ensuring donor engraftment across a MHC barrier without severe GVHD.

Introduction: β-thalassemia major requires a lifetime of transfusion and chelation therapy and despite improved chelation therapies, patients endure organ iron overload and increased hemolysis leading to organ injury and release of damage associated bio-markers. The structure of these markers are recognized by pattern recognition receptors (PRR) of the innate immune system as damage associated molecular patterns (DAMPs), which trigger inflammation and increased reactive oxygen species (ROS). The specificity of this recognition depends on PRRs, such as toll-like receptor 4 (TLR4), to provide the first line of defense against pathogens and DAMPS to initiate inflammation. Therefore, chronic organ iron loading is implicated in the chronic inflammation and morbidity of β-thalassemia major; however, the mechanism of how monocytes respond to iron loading in β-thalassemia remains largely unknown. This study investigated how chronic iron and heme overload affected innate immune cell morphology and expression of TLR4 and ROS by modeling THP-1 cellscompared to β-thalassemia monocytes. Methods: Cultured THP-1 monocytic cells were exposed to increasing concentrations of ferric citrate (0-250 μM) or heme (0-50 μM) for 24 hours or to chronic exposures of 40 μM ferric citrate for up to 3 weeks. Anti-human TLR4 phycoerythrin conjugated antibodies (TLR4-PE) were used to quantify TLR4 expression and 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) was used to measure ROS. Flow cytometry was done using a BD FACSCalibur. Peripheral-blood samples were obtained from 13 consenting β-thalassemia patients as part of the Novartis sponsored study investigating the effects of combined chelation therapy (CICL670AUS42T). Samples were also obtained from ethnically and age matched healthy controls. Peripheral-blood monocytes and THP-1 cells were gated on the parameters of forward and side scatter to stratify cells based on size and granularity, separating cells into two populations: larger more granular (LG) and smaller less granular (SG) cells. Results are reported as the MFI ratios of LG versus SG cells for TLR4-PE or DCFH-DA as a functional measure of the difference in TLR4 or ROS expression between these populations. Results: In vitro, LG THP-1 cells expressed 4-fold more TLR4 and 10-fold more ROS than SG cells (p < 0.001). Treatment of THP-1 cells with increasing concentrations of iron or heme for 1 day or 3 weeks, increased the ROS and TLR4 heterogeneity between LG and SG monocytes. The LG versus SG ratio of ROS production significantly correlated to the concentration of ferric citrate or heme added to the culture media (r = 0.64, p = 0.019 and r = 0.58 and p = 0.048, respectively). The mean ratio for iron but not heme treated THP-1 cells was significantly greater than for untreated cells (p = 0.008 and p = 0.406, respectively). Mean LG versus SG ratios of TLR4-PE MFI were 5.20 ± 1.56 for ferric citrate, 4.11 ± 0.90 for heme, and 3.78 ± 1.41 for untreated cells. We observed a similar TLR4 morphological heterogenic pattern in peripheral-blood monocytes from iron overloaded β-thalassemia patients. β-thalassemia LG monocytes had significantly greater TLR4 MFI than SG monocytes (LG mean = 11.91 ± 1.17, SG mean = 6.56 ± 1.02, p < 0.001). Long-term treatment of THP-1 monocytic cells for 3 weeks with 40 μM ferric citrate also resulted in the same phenomena regarding TLR4. No difference was observed in ROS production for control LG cells and SG cells; however, THP-1 cells treated for 3 weeks with 40uM ferric citrate revealed populations of LG cells that expressed 3 fold more ROS than SG cells. Conclusion: THP-1 monocytic cells and β-thalassemic peripheral-blood monocytes exhibit a morphological heterogeneity where LG cells express more TLR4 and in vitro, produce more ROS than SG cells. As TLR4 is one of the receptors for the initiation of inflammation, LG cells are likely greater contributors to the chronic inflammation experienced by β-thalassemia patients. Thus, we hypothesize that iron overload may give rise to monocytes that are larger and more granular and express more TLR4 and ROS. Disclosures Walter: Novartis: Research Funding. Porter:Shire: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy.

PURPOSE Few studies address the association of Chlamydia pneumoniae infection with pulmonary disease and outcome in patients with underlying pathology such as sickle cell disease (SCD). SCD patients are susceptible to the pulmonary disorder known as acute chest syndrome (ACS), where the etiology remains ill defined. The purpose of this study was to analyze the clinical course and outcome of C. pneumoniae-associated ACS among SCD patients as part of the National Acute Chest Syndrome Study.This was a longitudinal study of SCD patients presenting with ACS to multiple U.S. medical centers. Two hundred ninety-six SCD patients who developed ACS were tested by PCR for C. pneumoniae and by standard techniques for other respiratory pathogens. These infections were evaluated for association with ACS, clinical course, and complications.Forty-one (14%) patients with first episodes of ACS were PCR positive for C. pneumoniae. Compared with other infections, C. pneumoniae-infected patients were older, were more likely to present with chest pain, and had higher hemoglobin levels at diagnosis. Both groups had similar rates of respiratory failure and prolonged hospitalization. Of the 89 patients with single-pathogen infections, 27 (30%) were due to C. pneumoniae, 21% to Mycoplasma pneumoniae, 10% to RSV, 4% to Staphylococcus aureus, and 3% to Streptococcus pneumoniae.C. pneumoniae was the most prevalent pathogen in this study of ACS and was responsible for significant morbidity. Additional research is required to develop effective treatment guidelines for ACS.

Chronic transfusion therapy is being used more frequently to prevent and treat the complications of sickle cell disease. Previous studies have shown that the iron overload that results from such therapy in other patient populations is associated with significant morbidity and mortality. In this study we examined the extent of iron overload as well as the presence of liver injury and the predictive value of ferritin in estimating iron overload in children with sickle cell disease who receive chronic red blood cell transfusions. A poor correlation was observed between serum ferritin and the quantitative iron on liver biopsy (mean 13.68 ± 6.64 mg/g dry weight;R = 0.350, P = .142). Quantitative iron was highly correlated with the months of transfusion (R = 0.795, P

Introduction Complications of transfusional iron overload vary with the underlying hematologic condition and may be affected by inherent differences in non-transferrin bound iron (NTBI) generation between these conditions. We have previously reported high NTBI levels in Diamond Blackfan anemia (DBA) relative to sickle cell (SCD), despite lower serum ferritin and LIC associated with very low sTfR levels in DBA. This suggested that low transferrin iron utilization in DBA relative to SCD and thalassemia major (TM) accounted for high NTBI levels. It is known that pro-inflammatory cytokine IL6 will increase hepcidin synthesis thereby decreasing ferroportin expression on macrophages but it is not known whether high levels of inflammatory cytokines can overcome or limit the effects of iron overload in raising NTBI and transferrin saturation. Here we have examined additional factors that may affect NTBI levels in different forms of inherited anemias. The relationship of inflammatory markers, the hepcidin/ferritin ratio and monocyte ferroportin in these conditions to NTBI levels have been examined. The possible effect of vitamin C or vitamin D deficiency on NTBI has also been examined. Methods 15 iron-overloaded patients (5 from each group of TM, SCD, and DBA) with ferritin > 1500 g/dl or LIC > 7 mg/g dry wt, age 16, age 0 to 9 at initiation of transfusion and 10 to 20 years of transfusion exposure were enrolled from 3 sites in the US and Europe. 5 non-transfused healthy controls were also enrolled. Fasting, early morning blood samples (including WBC isolation) were obtained one day prior to transfusion. Chelation was held for 72 hours prior to each sample and samples taken pre-transfusion. Measurement of hepcidin, sTfR, GDF-15, transferrin saturation, NTBI and LPI was as described elsewhere. Inflammatory cytokine IL6 and IL10 were measured by multiplex bead fluorimetry. Ferroportin expression in circulating monocytes, a potential marker of its expression in resident macrophages of spleen, liver and bone marrow was measured by western blotting. Results Results shown in Table 1 are most notable for the following findings: in DBA, the inflammatory markers IL6 and IL10 are high as in SCD or TM. Furthermore plasma hepcidin levels and hepcidin/ferritin ratios are higher in DBA, than in SCD or TM. Despite these high values of hepcidin, IL6 and IL10, monocyte ferroportin levels and NTBI remain high in DBA. This suggests that chronically high levels of circulating hepcidin do not decrease NTBI in patients with low transferrin iron utilization (as in DBA) and that this latter effect combined with iron overload is the more powerful determinant in raising NTBI levels. If the circulating monocytes are a true reflection of resident tissue macrophages that phagocytize red cells, this would suggest that high hepcidin levels are insufficient to suppress ferroportin expression in the presence of severe iron overload. TGFb was most raised in SCD whereas TNFα, were similar in SCD, Thal and DBA. In SCD ferroportin levels on circulating monocytes were lower than DBA and Thal as well as being lower than control which could contribute to low transferrin saturation and low NTBI levels. Vitamin C levels were also lowest and this could contribute to iron retention within macrophages and hence the low NTBI levels observed in SCD. Conclusions Taken with our previous findings (ASH abstract 2012), our results are consistent with NTBI and Tf saturation being determined by an interaction of opposing effects, which vary depending on the underlying cause of anemia. NTBI and Tf saturation are increased by (a) iron overload, (b) low erythropoiesis though low utilization of transferrin iron. The findings in this study extension suggest that vitamin C deficiency in SCD could be a contributing factor to low NTBI and this requires further investigation. However the presence of a raised inflammatory cytokine and raised hepcidin appears to be insufficient to abrogate the combined effects of low utilization of transferrin iron and iron overload on raising NTBI in DBA. Disclosures: Porter: Novartis: Consultancy, Research Funding; Celgene: Consultancy; Shire: Consultancy. Walter:Novartis: Research Funding. Harmatz:Novartis: Research Funding; Shire: Consultancy, Honoraria, Research Funding, travel, travel Other. Vichinsky:Novartis: Honoraria, Research Funding.

Abstract 995 Background: β-thalassemia major (TM) is the paradigm for chronic transfusional iron overload, in which the extra-hepatic organ failure is best described. In Sickle Cell Disease (SCD), these consequences appear later and at a lower frequency. In chronically transfused Diamond Blackfan Anemia (DBA), extra-hepatic iron overload, although less well documented, appears to occur early and at high frequency. A Multicenter Study of Iron Overload (MCSIO) aims to explore how key candidate factors affect iron distribution; including inflammation, ineffective erythropoiesis, level of iron overload, and hepcidin synthesis. Plasma non-transferrin bound iron (NTBI) could be a key mechanism by which iron is delivered to tissues and may determine the propensity for extra-hepatic iron distribution. Here we focus on how markers of ineffective erythropoiesis (IE) and erythron expansion impact iron distribution, with particular reference to NTBI and iron distribution determined by MRI. Methods: Iron-overloaded patients (5 TM, 5 SCD, and 5 DBA) with ferritin > 1500 g/dl or LIC > 7 mg/g dry wt, age ≥16, age 0 to 9 at initiation of transfusion and 10 to 20 years of transfusion exposure were enrolled from 3 sites in the US and Europe. 5 non-transfused healthy controls were also enrolled. A detailed medical, transfusion and chelation history were obtained with standardized MRI evaluations for hepatic, cardiac, and pituitary iron deposition. Fasting, early morning blood samples were obtained one day prior to transfusion. Chelation was held for 72 hours prior to each sample. Results: Results are shown in the table as median values. DBA patients had the highest NTBI prior to transfusion despite having the lowest ferritin and LIC levels. GDF15 levels were highest in TM, with similar levels in SCD and DBA. EPO levels were nearly two orders of magnitude higher in DBA than TM or SCD. DBA patients also had the highest median cardiac R2*; two patients showing values above the control range. Whereas the median pituitary R2 in DBA was not above control, two of the patients had the highest R2 values, suggesting heavy iron deposition. EPO values in DBA are nearly two orders of magnitude higher that in SCD or TM despite similar pre-transfusion Hb values. GDF15 values are approximately three times controls, while soluble transferrin receptors (sTfR) values are almost undetectable. With SCD, no patients had increased cardiac iron loading, despite median SF and LIC being the highest in this group. Surprisingly all SCD patients had pituitary R2 values above the upper limit of normal. 1 TM patient had increased cardiac R2* whereas three had increased pituitary iron. In TM, NTBI was strongly correlated with GDF15 (Pearson's Rho=0.93) but in DBA, GDF15 was inversely correlated with NTBI (-.95). Conclusions: High GDF15 levels have been reported in conditions associated with IE, such as TM, but not in DBA. GDF15 reputedly suppresses hepcidin synthesis, thereby increasing iron absorption and potentially NTBI levels. The increased GDF15 in DBA, while sTfr remain less than controls, suggests that erythropoietic precursors do not reach the stage where sTfr are expressed and that this occurs at a later differentiation stage than GDF15. Increasing NTBI in TM with increasing GDF15 is consistent with IE contributing to NTBI formation, but the lack of this relationship in DBA suggest another mechanism for high NTBI. As the erythron is destroyed at a pre-hemoglobinised stage in DBA, IE would not contribute directly to NTBI formation. However, the extremely high EPO levels in DBA may inhibit hepcidin synthesis, as in other conditions, thereby increasing NTBI. This in turn may account for the extra-hepatic iron distribution demonstrated by MRI in DBA. The increased pituitary iron without cardiac loading in the heavily loaded SCD patients suggests that with prolonged exposure to heavy iron overload, the pituitary iron loading may be the first indicator of extra-hepatic deposition. Disclosures: Porter: Novartis: Consultancy, Research Funding. Walter:Novartis: Research Funding. Harmatz:Novartis: Research Funding; Ferrokin: Research Funding. Wood:Ferrokin Biosciences: Consultancy; Shire: Consultancy; Apotex: Consultancy, Honoraria; Novartis: Honoraria, Research Funding. Vichinsky:Novartis: Consultancy, Research Funding; ApoPharma: Consultancy, Research Funding; ARUP Research lab: Research Funding.

Abstract 998 Fetal hemoglobin (Hb F) induction is an effective therapeutic strategy in SCD. Widespread use of hydroxyurea (HU), the only approved anti-switching agent, has been limited by patient concerns about tolerability, patient compliance, and long-term use of a cytotoxic agent. There is a need for alternative anti-switching agents that are not cytotoxic and with different mechanisms of action. HQK-1001, an orally bioavailable short-chain fatty acid, promotes Hb F synthesis and prolongs erythroid survival and proliferation in pre-clinical models. In an earlier placebo-controlled Phase I/II study in SCD, HQK-1001 at 10, 20, and 30 mg/kg/day for 12 weeks was well tolerated and resulted in dose-dependent increase in Hb F. This randomized, open-label, dose escalation study evaluated the safety, pharmacodynamics (PD) and pharmacokinetics (PK) of HQK-1001 given at higher doses and for longer duration (NCT01322269). Patients with SCD ≥ 12 years of age were randomized to receive HQK-1001 at 30, 40, or 50 mg/kg daily for 26 weeks. Enrollment at 50 mg/kg was opened after an interim review of safety data at the 2 lower doses. Patients were stratified by HU at enrollment, and those on HU had to be on a stable dose for ≥ 6 months. HQK-1001 was discontinued if the patient was transfused. Oral iron was given daily if baseline plasma ferritin was < 700 ng/mL. Week 4 PK was evaluated in 4 patients at each dose. Pre-dose plasma concentrations were measured at each 4-weekly visits in all patients to verify compliance with dosing. Between April and September 2011, 52 patients were randomized to HQK-1001 at 30 mg/kg (n = 15), 40 mg/kg (n = 18), and 50 mg/kg (n = 19). There were 28 males and 24 females with a median age of 21 years (range, 12–46). The phenotype was Hb S-S in 45 and Hb S-β-thal-0 in 7, and 31 patients (60%) were on HU. The median duration on study drug was 114 days (range, 8–192), with 27 patients (52%) having discontinued HQK-1001 prior to completing the planned 26 weeks of dosing, 12 due to a transfusion and 15 for other reasons including withdrawal of consent and adverse events (AEs). The most common drug-related AEs, nausea (44%), vomiting (29%), somnolence (25%), headache (17%) and upper abdominal pain (17%), were usually graded as mild or moderate. Oral iron may have exacerbated upper gastrointestinal (GI) AEs. Dose limiting toxicities identified at 40 and 50 mg/kg doses consisted of gastritis (n = 3), somnolence (n = 2), pancreatitis (n = 1) and increased AST (n = 1). The maximum tolerated dose was established as 30 mg/kg/day and the protocol was amended to dose all patients at 30 mg/kg/day and discontinue oral iron. To further improve GI tolerability, the protocol was then amended to switch all patients to 15 mg/kg twice a day. No new drug-related severe toxicities were reported after stopping oral iron and dosing all patients at 30 mg/kg/day. Peak plasma concentrations were dose proportional. Average half-lives ranged from 9.8 to 11.7 hours and were dose independent. Plasma concentrations at 30 mg/kg were in the range shown to induce Hb F and erythropoiesis in pre-clinical models. Plasma concentrations were < 99% of the lower limit of confidence intervals in 16% of pre-dose samples collected at the scheduled times, suggesting non-compliance with HQK-1001 dosing in some patients. Of the 21 patients receiving HQK-1001 alone, Hb F increased in 18 patients (86%), with a mean increase of 2% (range, −2% to +10%), total Hb increased by a mean of 0.5 g/dL (range, −0.7 to 2.4 g/dL), and reticulocytes increased by a mean of 4.1% (range, to −4% to +15%). In 31 patients receiving HQK-1001 + HU, Hb F increased in 25 patients (80%), with a mean increase of 2.7% (range, −3% to + 10%), total Hb increased by a mean of 0.75 g/dL (range, −1.2 to + 1.8 g/dL), and reticulocytes increased by a mean of 1.4% (range, −6% to +15%). Covariate analysis showed significant correlation between change in Hb F at peak value and baseline ferritin (positive correlation, p = 0.008) and TIBC (negative correlation, p < 0.0001). This study demonstrated that HQK-1001 is well tolerated at 30 mg/kg/day. Plasma concentrations at this dose were in the range shown to induce Hb F and erythropoiesis in pre-clinical models. Hb F increased in most patients, both in HU and non-HU groups. HQK-1001 also increased erythropoiesis. Based on these positive results, a placebo-controlled Phase 2 study was launched to evaluate the PD, efficacy and safety of HQK-1001 at 15 mg/kg BID in SCD patients not currently treated with HU. Disclosures: Kutlar: HemaQuest Pharmaceuticals, Inc.: Research Funding. Reid:Haemaquest: Honoraria. Taher:Novartis: Research Funding, Speakers Bureau. Abboud:Novartis: Speakers Bureau; Pfizer: Research Funding; Sangart: Membership on an entity's Board of Directors or advisory committees. Buchanan:HemaQuest Pharmacuetical, Inc.: Research Funding. Ataga:HemaQuest Pharmaceuticals, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. White:HemaQuest: Consultancy. Johnson:HemaQuest Pharmaceuticals: Employment, Equity Ownership. Ghalie:HemaQuest Pharmaceuticals: Employment, Equity Ownership.

Abstract 1066 Fetal hemoglobin (Hb F) induction (anti-switching therapy) is an effective therapeutic strategy in sickle cell disease (SCD), both for reducing acute complications such as painful episodes and acute chest syndrome, and decreasing hospitalizations and transfusion requirements. Long term use of the only approved anti-switching agent, hydroxyurea (HU) has also been shown to improve survival. Despite this, HU is still not widely prescribed, ∼30% of patients are non-responders, and there are concerns regarding long term use of this cytotoxic agent. There is, therefore, a clear need for alternative anti-switching agents with different mechanism(s) of action, that are not cytotoxic, and that could be used either alone, or in combination with HU to enhance Hb F response. HQK-1001, an orally bioavailable short-chain fatty acid, was shown to promote Hb F synthesis and prolong erythroid survival and proliferation in transgenic mice and non-human primate models. In a Phase 1/2, dose-escalation, placebo-controlled study in 24 patients with SCD, HQK-1001 given at 10, 20, and 30 mg/kg/day for 12 weeks was well tolerated, showed dose-proportional pharmacokinetics (PK), and resulted in dose-dependent increase in Hb F (A Kutlar et al, Blood 2010; 116: Abstract 943). This randomized open-label Phase 2 study is being conducted to evaluate the safety, PK, and effect on Hb F of HQK-1001 administered at a higher dose and for a longer duration than previously studied. Patients with SCD age 12 years and greater were randomized to receive HQK-1001 at 30 or 40 mg/kg daily for 26 weeks. Enrollment at the 50 mg/kg dose level was opened after the Safety Monitoring Committee conducted a planned interim safety data review of the first 12 patients treated for 4 weeks. HQK-1001 is administered as 900 mg tablets, and daily oral iron supplementation is given to patients with plasma ferritin levels less than 700 ng/mL. A minimum of 14 patients stratified 1-to-1 by HU use at baseline will be enrolled at each dose level. Between 25 April 2011 and 5 August 2011, 39 patients have been enrolled and received HQK-1001 at 30 mg/kg (n = 14), 40 mg/kg (n = 14), and 50 mg/kg (n = 11). Patients were enrolled in North America (n = 18), Lebanon (n = 15) and Egypt (n = 6). Median age was 22 years (range, 12–47) and 7 (18%) were less than 18 years old. There were 20 (51%) males and 19 (49%) females. Patients had either Hb-SS (n = 34) or Hb-Sβ0 (n = 5), and 25 (64%) were on HU at baseline and continued HU while on study. Four patients have discontinued HQK-1001 per protocol following a transfusion to treat a SCD complication. One patient discontinued HQK-1001 due to pancreatitis. This patient was found to have a stone in the common bile duct and subsequently died postoperatively from multiorgan failure. The most common adverse events considered by the investigator as possibly drug-related were nausea in 10 patients (26%), abdominal/epigastric pain, vomiting, and headache in 5 (13%) each, and somnolence and dizziness in 3 (8%) each. Drug-related adverse events were graded as mild or moderate except for 1 case each of pancreatitis and gastritis graded as severe. No myelosuppression was observed. Assessment of HQK-1001 effect on Hb F and hemoglobin (Hb) is limited due to short follow-up. In 19 patients in which baseline and Week 4 data are available, the mean value at baseline for Hb was 8.9 g/dL (range, 7.4–11.4) and for Hb F was 1.11 g/dL (range, 0.15–3.33). Eight patients had data available both for Weeks 4 and 8. On Week 8, total Hb increased from baseline by a mean of 0.3 g/dL (range, −0.7 to 1.2) and Hb F increased by a mean of 0.14 g/dL (range, −0.19 to 0.42). The figure reports individual changes in Hb F from baseline to Weeks 4 (dark bars) and Week 8 (light bars), with “X” denoting the 4 patients on HU, and shows an increase in Hb F in 7 of 8 patients for that period. Enrollment is expected to be completed in August 2011 and updated results will be available at the meeting. In conclusion, the safety profile of HQK-1001 is consistent with results reported in prior studies and shows no overlapping toxicity with HU. Hb F is apparently increased in 7 of 8 patients with data available at Week 8, and this increase is seen both in patients receiving HU or not. Longer follow-up is needed to fully assess the safety of HQK-1001 and the extent of its effect on Hb F, total Hb, and SCD-related events. Disclosures: Aiello: HemaQuest Pharmaceuticals: Employment. Johnson:HemaQuest Pharmaceuticals: Employment. White:HemaQuest Pharmaceuticals: Consultancy. Ghalie:HemaQuest Pharmaceuticals: Employment.

Abstract 340 Transfusions are the primary therapy for thalassemia (thal) but have significant cumulative risks. The Thalassemia Clinical Research Network recently highlighted the increased rate of alloimmunization in this population1. In 2004, the CDC established a national blood safety monitoring program for thal. The goals of the program were to monitor blood safety and strategies for the management of complications. This report focuses on immune and non-immune transfusion reactions. Methods: The CDC Thalassemia Blood Safety Network is a consortium of thal centers that follow patients longitudinally to determine the transfusion-related complications. Serial demographic, physical, and laboratory data are collected along with blood samples analyzed at the CDC. Data collected includes ethnicity, genotype, phenotype, transfusion data, immunizations, type of red cell product, degree of antigen matching, and chelation therapy. Chronically transfused (CT) patients were defined as requiring at least 8 transfusions annually. Intermittently transfused (IT) patients received less than 8 transfusions annually. Statistical analyses included continuous variables, logistic regression, and multivariant analysis. Results: There were 407 patients including 327 CT patients and 80 IT patients. The genotype of chronically transfused patients included: TM (81%), TI (6%), E-Beta-Thal (6%), and Hemoglobin H/CS (4%). The average age of CT patients was 22.3 years ± 13 and 21.4 years ± 17 in IT patients. The average units CT patients received was 149 ± 103. Hemosiderosis occurred in both patient groups and correlated with transfusion history. The average ferritin (m/L) in each group, respectively, was 2261 and 689. 78% of the total population has received chronic chelation therapy. Multiple organ dysfunction was common in the population, including cardiac disease (13%), gonadal failure (17%), growth hormone deficiency (8%), hypothyroidism (8%), hypoparathyroidism (1.2%), diabetes (10%), and thrombotic events (5.4%). 45% of the population was splenectomized. Transfusion reactions occurred in 48% of patients, including allergic (45%), multiple etiologies (32%), febrile (17%), and hemolytic (5%). Transfusion-associated infection included 58 cases of Hepatitis-C and 4 cases of HIV. Two Hepatitis-C cases occurred after specific blood testing was initiated. Recent cases of bacteremia, malaria, and Babesiosis have been documented. 21% of CT patients and 13% of IT patients developed an alloantibody. The most common antigen specificity included E (25%), Kell (13%), C (9%), Jka (5%), Kpa (4%), HLA (4%), V (3%), c (3%), D (2.5%), WA-1 (2.5%), and S (2.5%). 45% of alloimmunized patients had multiple antibodies. Race, transfusion burden, age and splenectomy predicted alloimmunization. Alloimmunization was found in 31% of splenectomized patients vs. 10% of non-splenectomized patients (p Autoantibodies occurred in 6.5% of the population and increased with age and splenectomy. Alloimmunization increased the risk of autoantibodies: 26% of patients with an alloantibody had an autoantibody whereas only 2% of patients without alloantibodies had an autoantibody (p Local institutional policies were the major determinant in the type of units administered. In the last year, 32% of the units were washed and 80% radiated. 40% of patients received standard ABO matching, 47% limited phenotypic matching, and 12% full extended matching. Conclusion: Transfusion-related morbidity is a major problem in thal. Hemosiderosis immunologic and non-immunologic reactions are common. Transfusion-related infections have decreased but new, emerging pathogens have been noted. Disclosures: No relevant conflicts of interest to declare.

Abstract 254 Clinical experience and research with sickle cell patients and those with other genetic diseases suggests that the period of “transition,” in which patients move from pediatric care to adult-centered clinical care, is a period of high health services utilization. Young adult patients may not have learned to effectively manage disease symptoms and may not be connected to a “medical home” or have established a relationship with a primary care physician or adult hematologist. Further, these patients may not have insurance coverage previously provided by parents or by public pediatric insurance programs. As part of a collaborative agreement through the Centers for Disease Control and Prevention (CDC) and the National Heart, Lung & Blood Institute (NHLBI), California and five other states are conducting epidemiologic surveillance to determine the prevalence of hemoglobinopathies as well as health services utilization. Such data are essential to inform allocation of resources to meet the medical and social service needs of patients. Within the state, this project is a collaborative effort among the CA Dept. of Public Health Genetic Disease Screening Program, Children's Hospital Los Angeles and Children's Hospital & Research Center Oakland. Using administrative data obtained as a part of this effort, we describe emergency room (ER) utilization patterns among young adults with sickle cell disease. The CA Office of Statewide Health Planning and Development has collected data on ER utilization for the years 2005 – 2008. Using ICD 9 codes beginning with 282.6 to identify sickle cell-related ER visits during those years, we report usage patterns by patient age, gender, and payer type. To calculate risk of repeat ER visits, we used a negative binomial regression model (with 1 visit as the baseline for analysis, rather than 0 visits, due to the limitations of the data set). The following means and counts are adjusted to account for this shift. Analyses were conducted using SAS 9.1. The mean number of ER visits among sickle cell patients in the data set was 3.36 per year and 54% of visits were made by women, but gender differences in average visits per year per patient (3.18 female, 3.60 male) were not statistically significant. Medi-Cal (Medicaid) was the primary payer for 47% of visits during this time frame, and patients with Medi-Cal averaged nearly one additional visit per year (3.82 visits) compared to patients with other forms of payment (3.04 visits). Among patients seen at any time during the four years and controlling for gender and payer type, we found a 78% increase (IRR 1.78, 95% CI 1.59, 2.00) in risk of visiting the ER a second or subsequent time in a given year among the 20 to 30 year old group compared to all other age groups, a four fold increase (IRR 4.22, 95% CI 3.61, 4.93) in risk of a second or subsequent visit in a year compared to the group aged 10 to 20 years, and a 30% increase (IRR 1.34, 95% CI 1.16, 1.55) compared to the group 30 to 40 years of age. Average number of visits in the transition age group was 4.53 per year, compared to 1.93 per year in the 10 to 20y group and 3.56 in the 30 to 40y age group. The number of individuals visiting the ER per year was higher in this age group compared to the two adjoining age groups (520 individuals on average per year for 20 – 30y, vs. 311 per year for 10 – 20y and 355 for 30 to 40y). The increase in visits per year of age can be seen (Figure 1) to begin at age 18 or 19 and continue to approximately age 30. The proportion of patients with no insurance coverage increased from 8% in the 10 to 20y age category to 19% of patients in the 20 to 30y age category, and remains high for the subsequent age categories (11 to 17%). The transition period from pediatric care to adult care in California sickle cell patients is marked by a dramatic increase in emergency room visits (both more patients visiting and more visits per patient) compared to other age groups. ERs are also visited significantly more often by uninsured sickle cell patients in this age group than other age groups. Patients in this age group would likely benefit from access to a medical home model of care.Figure 1.Mean Annual Number of Visits by Age of Patient among Those Seen in ER with SCD-related ICD 9 Codes, California, 2005–2008Figure 1. Mean Annual Number of Visits by Age of Patient among Those Seen in ER with SCD-related ICD 9 Codes, California, 2005–2008 Disclosures: Coates: Novartis: Research Funding, Speakers Bureau.

Abstract 3221 Background: Most adult sickle cell anemia patients have received transfusion therapy. However, prospective studies evaluating the efficacy of transfusions in preventing sickle cell-related complications are lacking. The Phase II Neuropsychological Adult Sickle Cell Anemia Study is a randomized trial of chronic transfusion vs. standard of care in patients with abnormal neurocognitive function in order to determine the safety and benefits of transfusion therapy on neurocognitive function. A secondary goal of the study is to evaluate the benefit of chronic transfusion on the frequency and severity of acute sickle cell events; this is a preliminary report of this specific aim. Methods: Eligibility required normal neurological exam, WAIS III PIQ score ≤ 90, hemoglobin ≤ 9 g/dL, hemoglobin SS electrophoresis, and age between 21 and 55 years. Patients were randomly assigned to receive either standard care or transfusions. The transfusion goal was to maintain a hemoglobin of 2 g/dL rise over baseline with matched red cells for D, C/c, E/e, and Kell antigens. The protocol required simple transfusions at approximately 4 week intervals. Chelation therapy was not part of the study design. Patients underwent serial clinical and laboratory evaluations with central analysis of all clinical and transfusion events and complications. Laboratory testing of subjects in the transfusion arm included quantitative hemoglobin S/A, hemoglobin concentration, ferritin levels, and red cell antibody screening; a full hematology/chemistry panel was performed for all subjects at baseline, the study mid-point, and at the end of the study. Results: There were 20 patients in the transfusion arm (TX arm) with a mean age of 29 years vs. 16 patients in the standard care arm (SC arm) with a mean age of 30.5 years. The baseline data in the TX arm was similar to the SC arm: hemoglobin 7.8 vs. 8.0 g/dL; hematocrit 22.6% vs. 23.1%; hemoglobin F 10.5% vs. 12.5%. Thirty-five percent of patients randomized to the TX arm had a history of acute chest syndrome (ACS) vs. 31% in the SC arm; 30% of patients in the TX arm were on hydroxyurea compared to 50% in the SC arm. The TX arm patients have received an average of 5.6 transfusions (2 units per transfusion) with only one subject requiring an acute transfusion (5%); in contrast, 4 SC arm patients (25%) were transfused for acute events for a total of 7 units (average 1.8 per patient). The transfusion therapy improved the average hematologic status of patients: hemoglobin S% decreased from 85% to 32% (p=0.0003); hemoglobin and hematocrit increased from 7.6 to 9.4 g/dL (p=0.0052) and 22% to 28%, (p=0.007), respectively. Bilirubin declined from 3.6 to 2.4 mg/dL (p=0.042). In contrast, only bilirubin showed a significant decrease in the SC arm. In the TX arm, serum ferritin rose an average of 1318 to 2368 (p=.001); there was no change in liver function. There were no clinical transfusion reactions in the 120 study transfusions (360 units); however, one patient on routine screening reported a transient anti-D antibody without clinical or laboratory changes. Clinical Results: Adverse events were higher in the SC arm. Total number of adverse events in the TX arm were 23 (1.2 per person) vs. 66 in (4.1 per person) in the SC arm. There were 5 hospitalizations in the TX arm and 21 in the SC care arm, with a median number of hospitalized days per hospitalization of 5.0 and 6.0 respectively. The total number of serious events was 6 in the TX arm (0.3 per person) vs. 23 in the SC arm (1.4 per person). The total number of vaso-occlusive events in the TX arm were 14 (0.7 per person) vs. 57 (3.6 per person) in the SC arm. Acute pulmonary events occurred in 25% (4 patients) of the SC arm vs. none in the TX arm. Conclusions: This is preliminary data from the first prospective randomized study of the safety and efficacy of transfusion therapy in adults with SCD. We demonstrate the safety of transfusion therapy. Compared to standard therapy, transfusions improve or stabilize critical laboratory markers, decrease serious sickle cell anemia-related adverse events, and decrease in hospitalizations. Increase in ferritin is an expected outcome in transfused patients since chelation was not a part of this transfusion protocol. On completion of the study, the potential benefits of transfusion therapy on sickle cell disease morbidity including neurocognitive function will be reported. Disclosures: Field: Novartis Pharm: Honoraria.

Abstract 943 Definitive therapies to reduce the underlying pathology in sickle cell syndromes are still needed, particularly non-cytotoxic therapeutics which could be used either alone or in combination with hydroxyurea. Increased fetal hemoglobin (HbF) levels correlate with reduction in organ damage and improved patient survival. An oral, promoter-targeted fetal globin gene stimulant, HQK-1001, which also prolongs erythroid survival and proliferation, has demonstrated favorable pharmacokinetic (PK) and safety profiles in normal volunteers in a Phase 1 clinical trial. Accordingly, a randomized, blinded dose-ranging Phase 1/2 trial was performed in 24 adult patients with sickle cell disease (including HbSS or S/ß thalassemia). The study therapeutic was administered once daily for two 6-week cycles of daily therapy with a 2 week treatment break between the two cycles. Three dose levels (10, 20, 30 mg/kg/dose) were studied sequentially, with 4 placebo treated subjects. 21 patients were evaluable. Five patients received active drug at the lower two dose levels; 7 patients received active study drug at the 30 mg/kg dose level. HQK-1001 was well-tolerated with no significant drug-related adverse events. Increases in HbF levels were observed at all dose levels with the highest effects observed at 30 mg/kg, where 5 of 7 treated patients responded with a mean peak increase of 2.6% HbF (absolute 0.2 g/dl, p=0.04) above baseline. HbF increased both in patients who did, and who did not, take concomitant hydroxyurea. A mean peak increase in total hemoglobin of 1.3 g/dL (range 0.9 to 2.4) above baseline was also observed in these HQK-1001-treated patients. F-reticulocytes and F-cells increased by 20–33% and 6–18%, respectively, in the 5 responders at the 30 mg/kg dose level. LDH declined in 4 of 5 responding subjects receiving 30 mg/kg doses. Fetal globin mRNA increased by 4- to 9-fold over baseline throughout the study period in treated patients and was still increasing at the end of the dosing period, implying that HbF expression had not yet peaked. Other fetal globin inducing agents, such as hydroxyurea require 6–9 months of treatment for optimal effects on HbF to be achieved. Therefore, the findings of HbF induction and rises in total Hgb in 70% of subjects with short treatment duration in the current study indicate that longer trials of HQK-1001 are warranted to evaluate potential therapeutic effects on HbF expression and anemia more definitively in sickle cell disease. Disclosures: Kutlar: HemaQuest Pharmaceuticals, Inc: Research Funding. Vichinsky:HemaQuest Pharmaceuticals, Inc: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Neumayr:Novartis : Honoraria, one time honoraium 10/09; NIH: Research Funding. Labotka:HemaQuest Pharmaceuticals, Inc: Research Funding. Keefer:HemaQuest Pharmaceuticals, Inc: Research Funding. Shen:HemaQuest Pharmaceuticals, Inc: Research Funding. Boosalis:HemaQuest Pharmaceuticals, Inc: Equity Ownership, Research Funding. Thomson:HemaQuest Pharmaceuticals: Employment, Equity Ownership. Bobbitt:HemaQuest Pharmaceuticals, Inc: Employment, Equity Ownership, Patents & Royalties. Wallis:HemaQuest Pharmaceuticals: Consultancy, Equity Ownership. Johnson:HemaQuest Pharmaceuticals: Employment, Equity Ownership. Berenson:HemaQuest Pharmaceuticals, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Perrine:HemaQuest Pharmaceuticals, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Abstract 264 Background: Approximately half of sickle cell anemia (SCA) patients will develop aseptic necrosis (AVN) of the hips, with the majority of cases progressing to total collapse of the femoral head. Total hip arthroplasty (THR) in patients with SCA has been associated with high rates of perioperative complications and eventual failure of the prosthesis. Previous studies have suggested that hip coring decompression (HCD) is effective in decreasing pain and slowing the progression of AVN. In the most recent study of HCD in SCA, the mean surgical time was 1.1 hours and anesthesia time 2.1 hours; associated blood loss was 56cc. The length of hospital stay (LOS) was 5 days with a mean of 3 days postoperatively. We report a surgical approach designed to decrease surgical time while at the same time improving perfusion to the effected tissue with repeated small bone fenestrations. Patients and Methods: From 11/1/2009 to 7/1/2010, 8 patients (10 hips) with SCA underwent HCD for femoral AVN: 3 females and 5 males with an average age of 31.3 years (median 25.5, range 11 to 50). 5 patients had SS and 3 SC disease. Seven hips were diagnosed as Ficat stage II and 3 as stage III. Physical exams and pain assessments were performed before surgery and at follow-up by the same orthopedic surgeon. The clinical protocol includes a two day hospital stay: admission the day before surgery with overnight hydration at 1.5× maintenance fluids, postoperative management of pain and hydration, and discharge after PT evaluation and instruction. Patients are fully ambulatory at discharge and given exercise instructions by physical therapists. Description of Procedure and Physical Therapy Plan: Under anesthesia, patients are placed in a lateral position on a bean-bag and bony prominences are well padded; an axillary roll is used. The hip, thigh, and mid part of the leg are sterilely prepared and draped, allowing rotation of the leg. The fluoroscopic C-Arm is placed underneath the bed, so that a true AP of affected hip is obtained. The fluoroscopic image determines the starting point for the initial 0.5 cm incision with a 15-blade. The drill (with a 5.0 bit) is then advanced to the proximal lateral cortex of the femur, distal to the greater trochanter. Under radiographic guidance, drill position is confirmed and advanced to the affected area of the femoral head. The drill is then withdrawn to the cortex (but within the cortical window) and advanced in different directions to achieve 3 adequate core channels. Prior to applying dressings, a six-inch long 18-gauge needle on a 10 cc syringe, containing 0.25% Marcaine with epinephrine is placed into the affected hip joint, under fluoroscopic guidance, and a small volume of the anesthetic is injected for relief of postoperative pain and pain associated with synovitis. Results: The average surgical and anesthesia time in minutes were: 15.9 ± 6.6 and 53.4 ± 18.1 respectively; mean blood loss was less than 10 cc. Three procedures were performed under conscious sedation without tracheal intubation. Two procedures were performed during an admission for acute pain; the remaining 8 were scheduled surgical admissions. The average LOS for the scheduled procedures was 5 days (3.5 days postoperative). No complications were reported in the immediate or 6-week postoperative periods. In this series of 10 hips, all patients were fully weight bearing and ambulatory at discharge. Prior to surgery, all 10 hips were rated as a 10 on a 10-point pain scale. At the 6 week follow-up exam, 8/10 hips were rated as pain free, one hip was rated as a 1/10 and one hip remained a 10/10. The two patients undergoing surgery during acute pain episode involving the affected hip received immediate relief and were able to be discharged early. Conclusion: The modified HCD technique utilizing small, repeated fenestrations is safe and is associated with reduced operative times, reduced anesthesia time, and negligible blood loss compared to previous studies of HCD for femoral AVN in SCA. Preliminary data indicates it is effective in decreasing the pain associate with AVN. We plan to follow these and future patients for 5 years with serial radiographs and evaluations utilizing the validated, reliable Children's Hospital Oakland Hip Evaluation Scale. Disclosures: No relevant conflicts of interest to declare.

Abstract 4269 Therapeutic regimens that combine two iron chelators may enhance chelation efficiency by improving access to different tissue iron stores and control of the toxic labile iron pool. The combination of two chelators can reduce toxicity through averting the need for high doses of a single drug, but it is essential to establish the safety such regimens. We therefore explored the combined use of deferasirox (DSX) and deferoxamine (DFO) in patients with transfusion-dependent thalassemia who had failed standard chelation therapy with single drug. Patients were eligible if the liver iron concentration (LIC) >15 mg/g dry liver-weight or if iron-induced end organ injury was present. Subjects were monitored for hepatic and renal toxicity, visual or auditory changes, and the development of new complications from iron overload. The ability of the combined therapy to control systemic iron burden (serum ferritin and LIC) and myocardial iron overload (MRI T2*) was evaluated. We also measured changes in plasma levels of non-transferrin bound iron (NTBI) and labile plasma iron (LPI). Fifteen subjects were enrolled in 3 groups: adults with LIC 15 mg/g (group B), and children 8–18 years with LIC >5 mg/g (group C). The duration of therapy was 52 weeks. DSX (20-30 mg/Kg) was administered daily and DFO (35-50 mg/Kg/infusion) was infused on 3–7 days/week (as 8–12 hour infusion) based upon the degree of iron overload present at baseline. At the initiation of the study, the mean daily dose of DFO was 16, 33, and 17 mg/Kg/day and mean DSX dose was 21, 25 and 22 mg/Kg/day for groups A, B and C, respectively. At the conclusion of the trial, the median LIC declined by 48% from 10.8 mg/g (3.9-34.8 mg/g) to 5.7 mg/g (1.0-24.0 mg/g, p=0.003). The median ferritin fell by 43% from 2030 ng/mL (1000-5230 ng/mL) to 1150 ng/mL (421-5260 ng/mL, p=0.008). Myocardial iron in the 3 subjects who had T2* No significant toxicity or unusual adverse events were observed with combined chelation therapy in this group of high-risk patients with thalassemia. Elevation of serum creatinine or ALT was not observed in any subject. One subject from group B died at 9 weeks from start of trial from sepsis. One subject interrupted DSX therapy because of abdominal pain. In all other cases the treatment was well tolerated and no dose adjustment or suspension of therapy was required on account of toxicity. Protocol-mandated modification of treatment (temporary cessation of DSX or DFO) occurred in three subjects owing to a marked fall in serum ferritin and LIC. These results suggest that simultaneous administration DSX and DFO is well tolerated and has low potential for toxicity. Combined chelation therapy appears to be effective in rapidly reducing systemic iron burden, lowering myocardial iron, and controlling plasma NTBI and LPI in patients at risk of developing end-organ damage. Disclosures: Harmatz: Ferrokin: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Vichinsky:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Abstract 2425 Poster Board II-402 Introduction: Unrelated cord blood transplantation (CBT) is associated with a risk of graft rejection due in part to a limiting cellular content of the CB unit. Increasing the cellular content of the CB unit mitigates the graft rejection risk, but methods to use adjuvant immuno-modulatory cell co-infusions have also been tested with some success. We have investigated the co-infusion of photochemically (psoralen S59) treated mature donor T lymphocytes in a major histocompatibility complex (MHC) [H2-haplotype] mismatched murine transplant model as a new method to facilitate engraftment of donor CB cells. Methods: We analyzed the rates of donor hematopoietic cell engraftment, graft versus host disease (GVHD), and long-term survival in H2 haplotype disparate (C57BL/6®AKR) mice after CBT. Three different experimental groups were transplanted after sublethal radiation. Group 1 received allogeneic full term newborn peripheral blood alone, group 2 was transplanted with the same donor cells and unmanipulated donor T cells, and group 3 was transplanted with the similar donor cells and psoralen (S-59) treated donor T cells. Results: We observed a low rate of donor engraftment after transplantation with cord blood alone (Group 1). There was better engraftment but a high rate of fatal GVHD after transplantation with cord blood and unmodified donor T-cells (Group 2). The best results were observed after transplantation with 3 × 106 nucleated cord blood cells and 9 ×106 S-59 treated T cells (Group 3b). The engraftment rate was 75% compared to 12.5% after transplantation with 6 × 106 CB cells alone (p=0.04). The long-term survival in group 3 was 100% and the rate and severity of GVHD were minimal. Engraftment observed after CBT with unmodified donor T-cells (group 2) was accompanied by severe GVHD and poor survival. Donor myeloid, B cells and T cells were documented in the spleen and bone marrow of Group 3 mice by 30 days after CBT, although full hematological recovery was delayed until 50-60 days after CBT. Conclusions: These results show improved cord blood engraftment kinetics across a disparate H2 haplotype by adding psoralen-treated donor T lymphocytes. Co-transplantation of psoralen treated lymphocytes with CB cells facilitated durable engraftment of donor MHC high/c-kit+ cells in the marrow and splenic compartments with complete but delayed hematopoietic recovery. The low GVHD risk and excellent long-term survival observed in this murine model suggests the potential for clinical application. Disclosures: No relevant conflicts of interest to declare.

Abstract 3155 Poster Board III-92 Background Standard of practice recommends slow transfusion (i.e., 5 ml per kg over 4 hours) for children with a hemoglobin level less than 5.0 g per dL secondary to severe chronic anemia (Principles and Practice of Pediatric Oncology. 4th ed. 2002:1206). Transfusion-associated circulatory overload (TACO) remains a theoretical problem but usually manifests in patients with poor underlying cardiopulmonary status and specifically in the very young (i.e., neonates) and the very elderly (ISBT Science Series 2009;4:63-71). As no evidence exists as to what rate of transfusion for children with severe chronic anemia would be unsafe, our Pediatric Intensive Care Unit (PICU) has been utilizing a more liberal transfusion practice intermittently for the last ten years. Methods After institutional review board approval, we reviewed all patients admitted to the PICU over the last ten years with a hemoglobin less than 5.0 g per dL. Patients transfused an average of less than 5 ml per kg over 4 hours were excluded. The remaining patients transfused greater than 5 ml per kg over 4 hours had a more extensive chart review and those patients diagnosed by ICD9 code with acute blood loss were further excluded. For the remaining patients who met the criteria for severe chronic anemia and received greater than 5 ml per kg averaged over 4 hours, we documented vitals including heart rate, respiratory rate, systolic and diastolic blood pressure, oxygen saturation and inputs/outputs as well as diuretic usage and chest radiograph findings to analyze for signs of TACO. We further compared these patients to a control group that received slow transfusions. Statistical analysis was done using one- and two-sample t-tests. Results 17 patients with a median age of 2.2 years (range 4 mos-12 yrs) received transfusions which met our inclusion and exclusion criteria, with a median transfusion rate of 10 ml/kg/4 hrs (range 6.8-49.6). No patient had an adverse event or changes in their vitals consistent with TACO. Heart rate dropped significantly although not statistically more than the randomly assigned control population (one-sample t-test, t=3.277, p=0.002, two-sample t-test, t=0.68, p=0.25). No patient in either group had a new oxygen requirement or worsening of their chest radiograph. Diuretics and oxygen supplementation were used in both groups empirically only. Discussion TACO appears to be a theoretical risk in the normal pediatric population; therefore, slow transfusion is likely an unwarranted anecdotal practice for children with severe chronic anemia. Both the study patients and control group had a statistically significant drop in heart rate with transfusion, emphasizing the safety of any rate of transfusion in our population. Rate of transfusion must be based on multiple factors including convenience, timeliness of procedures and of transport to an appropriate care facility, risk of alloimmunization, wastage of blood, stress for the family and need for PICU monitoring. Jayabose et al. reported similar results in 1993 (Am J Pediatr Hematol/Oncol 1993;15:324-7), but institutional practice has not changed. Although with a small preliminary sample size, we report a similar retrospective safety profile emphasizing the lack of risk for more liberal transfusion rates in pediatric patients with severe chronic anemia. Disclosures No relevant conflicts of interest to declare.

Abstract 2021 Poster Board I-1043 Therapeutic regimens that combine two chelators have the potential to improve iron excretion while avoiding toxicities associated with high doses of single agents. This pilot study was designed to explore the safety of the combined treatment with deferasirox (DFX) and deferoxamine (DFO) in individuals with transfusion-dependent thalassemia and iron overload who had failed standard therapy. Subjects underwent baseline evaluation of liver iron, cardiac iron, cardiac function and target organ damage, and were enrolled in 3 groups (n=5 in each group) - Group B: adults with liver iron concentration (LIC) >15 mg/g dry weight, group A: adults with LIC >5 and 5 mg/g dry weight plus iron related organ dysfunction. The duration of therapy was 52 weeks, with DFX (20-30 mg/Kg) given daily and (DFO 35-50 mg/Kg/infusion) given for 3-5 days/week (groups A and C), or 5-7 days/week (group B). Subjects were monitored for hepatic and renal toxicity, visual or auditory changes, and development of new symptoms. Changes in serum ferritin, LIC (ferritometer), cardiac function (MRI) and myocardial iron (MRI T2*) were monitored. We have enrolled 14 subjects (target 15 subjects) with a median follow up of 29 weeks (range 18-52). The mean daily dose of DFO was 16, 33, and 17 mg/Kg/day for groups A, B and C, respectively, at the start of the study. The corresponding mean DFX dose was 21, 25 and 22 mg/Kg/day. At the end of 26 weeks, the mean LIC (mg/g dry wt) in evaluable patients declined from 13.0 (3.9-21.7) to 10.6 (0.60-18.3, p=0.015), and the mean ferritin (ng/mL) fell from 2631 (1000-5230) to 2158 (319-5845, p=n.s.). Cardiac evaluation revealed that mean MRI T2* (msec) improved from 22.7 (6.7-32.6) to 25.5 (10.7-38.1) and the mean LVEF (%) from 63.4 (47.5-68.5) to 64.3 (53.4-72.2), but these changes were not statistically significant. No subject developed evidence of significant myocardial iron (T2* Disclosures: Lal: Novartis: Research Funding. Harmatz:Novartis: Research Funding. Vichinsky:Novartis: Consultancy, Research Funding.

Background. Brain dysfunction may be the most important and least studied problem afflicting the aging SCD population. 25% of neurologically intact pediatric SCD patients have NP dysfunction and silent CNS infarction. In children, age is associated with progressive decline in NP scores suggesting adults are at risk for progressive brain injury and NP decline. Objective. To determine the extent of NP impairment, the prevalence of MRI abnormalities, and their relationship in neurologically asymptomatic adult SCD patients compared to national norms and matched controls. Methods. Patients (21–55 yrs) with HbSS, normal neurologic exams and no history of stroke or abnormal neuroimaging, were recruited from 11 centers and screened for mental status and depression. The patient to control ratio goal was 3:1. After consenting, participants completed NP tests that assessed verbal and nonverbal intelligence, academic achievement, executive functioning, processing speed (PS), attention, and memory. Tests included the Wechsler Adult Intelligence Scale (WAIS-III), the Wechsler Memory Scales (WMS-III), the Woodcock-Johnson Tests of Achievement (WJ III), the Test of Everyday Attention (TEA), and others. Participants underwent standardized brain MRI read for atrophy and lesions. Volumetric analysis (vMRI) quantitated white and grey matter. Results. This is a report of 138 of the 150 planned SCD subjects and 37 controls: 62% female, 21–29 yrs, with mean hemoglobin (Hb) 8.2g/dl. 32% and 39% of patients scored one standard deviation (below 86) on the WAIS-III Performance IQ (PIQ) and PS index (PSI) scores compared to 16% in national norms. 26% and 22% of patients scored below 86 on the WMS-III visual immediate and immediate memory scales compared to 16% in national norms. Controlling for age, gender, and education, patients and controls differed significantly on the WAIS-III PSI Score, −14.1 (95% CI of −19.2 to −9.0) and the WJ-III including reading, math and following directions. Subtests of attention and flexibility of thought of the TEA significantly decreased with age in patients but not controls. In 82 patients with MRIs, 63% had an abnormal MRI or NP dysfunction, 38% had atrophy and/or ischemic lesions, and 18% had ischemic lesions only. Low PIQ and PSI were significantly associated with ischemic lesions. In vMRI, adjusting for age and gender, hippocampal volume in patients was 541.1 μL < controls (95% CI of 212.0, 870.3) and CSF volume in patients was 16 mL > controls (95% CI of 1.7, 31.5). These dfferences were significant. Patient Hb was a significant independent predictor of verbal IQ, PIQ, PSI, math, and executive function (Pearson r = .20 –.28). Conclusion. NP dysfunction and/or undetected brain injury affect the majority of neurologically intact adults with SCD, especially in areas of executive functioning, reading and math fluency. Patients with lower Hb have lower IQ scores. Ischemic lesions, alone, do not account for the extent of the NP impairment observed. Hb, age, and hippocampal volume were predictive of NP dysfunction, suggesting a link between reduced oxygenation, neuronal loss, and cognitive impairment. This supports the importance of a transfusion trial to improve NP function.

BACKGROUND: Iron-induced cardiomyopathy has been extensively described in thalassemia (THAL) patients. Left ventricular (LV) dysfunction is the leading cause of death in THAL, with prevalence estimates ranging from 6% to 23%. Recent MRI techniques confirmed that T2* measurements consistent with elevated cardiac iron are associated with LV dysfunction and early mortality. Transfusion therapy is being increasingly used for the treatment and prevention of complications in sickle cell disease (SCD). By adulthood, the majority of SCD patients will have received multiple transfusions and nearly 1/3 will be iron-overloaded. However, cardiomyopathy, its prevalence, and the role of iron toxicity have not been studied in SCD. The Multicenter Study of Iron Overload, a 5-year prospective natural history study, enrolled 152 transfusion dependent THAL, 204 chronically transfused SCD (txSCD) and 64 control SCD in order to compare the effects of iron toxicity in these two diseases. We compared the prevalence of LV dysfunction and its relationship to iron-toxicity in THAL, txSCD and control SCD. METHODS AND RESULTS: Baseline or year 1 echocardiograms (ECHOs) were available in 45% of the patients (80 THAL, 94 txSCD and 16 SCD controls) and reviewed for evidence of LV dysfunction, defined as an ejection fraction ≤ 55% or shortening fraction ≤ 28%. Pulmonary hypertension (PHT) was defined as a tricuspid regurgitant jet velocity (TRV) ≥ 2.5 m/s or pulmonary artery pressure (PAP) ≥ 35 mmHg. ECHOs reported as normal, even without TRV or PAP recorded, were assumed to be negative for PHT. At study entry, THAL and txSCD patients were severely iron over-loaded and their average ferritin and liver iron concentrations were not significantly different: 3506 g/dl and 20 mg/g dry weight. (Serum ferritin in the control SCD was 120 g/dl.) The average age of the patients was 30.3 ± 12 yrs, and did not differ across the three groups. LV dysfunction was found in 22% THAL; THAL patients with LV dysfunction had been transfused longer than those with normal ECHOs (26.5 vs. 21.1 yrs, p=. 03). A subgroup of THAL was screened with cardiac MRI: 11/21 (52%) had evidence of cardiac iron deposition, 4 of these patients (36%) had LV dysfunction. In THAL screened with MRI, all patients with LV dysfunction had cardiac iron deposition. LV dysfunction was seen in 14% of txSCD but in 0% of the control SCD. txSCD patients with LV dysfunction were older (43.7 vs. 28.5, p CONCLUSIONS: LV dysfunction is common in transfusion dependent THAL and associated with duration of transfusion and iron deposition. In SCD, patients with cardiomyopathy were chronically transfused, older, and more likely to have PHT. SCD patients are developing iron overload similar to THAL; cardiac MRI studies are essential for the evaluation of iron deposition and its relationship to cardiomyopathy.

Improvements in transfusion and chelation treatment have led to increased survival of patients with thalassemia (THAL), however, HPG axis dysfunction continues as the most prevalent complication of iron-overload in THAL. The critical target organ for HPG axis dysfunction in thalassemia is the anterior pituitary gland. In a pilot study on iron-induced endocrinopathies in chronically transfused thalassemia and sickle cell disease (SCD) patients, we developed MRI methods to quantitatively assess pituitary iron by measuring the transversal relaxation rate (R2), the anterior and posterior volume, and anterior pituitary height. We examined the hypothesis that iron will be elevated in the pituitary of heavily transfused thalassemia patients, but gland volume and height will correlate more closely with function. We scanned 13 subjects (controls 8, HbE-thalassemia and thalassemia major 4, iron-overloaded SCD 1) with a total of 17 measurements in a 1.5 Tesla imager of Children’s Hospital Oakland (Philips Gyroscan®) using a quadrature head coil. Two of 4 thalassemia patients were on hormone replacement treatment. The relaxation rate R2 of the anterior pituitary gland was determined from 2 or 3 sagittal slices (3 mm slice thickness, 0.3 mm gap, manually traced ROI covering more than 60% of the gland within each slice) by a turbo-spin echo sequence acquiring 8 evenly spaced echoes (TE = 15, 30,..., 120 ms, TR = 2500 ms). Anterior and posterior pituitary volumes were analyzed from sagittal slices by manual tracing (3D FFE, 1 mm3 isotropic voxel, TE = 4.6 ms, TR = 9.8 ms, a = 15°). Anterior pituitary height was obtained from routine T1 weighted sagittal multi-slice spin echo images (slice thickness 3 mm, gap 0.3 mm). Liver iron concentration (LIC) by SQUID biosusceptometry was used for total body iron estimation. A reproducibility of 2.6 % (COV) was determined in a normal subject for a mean R2 = 11.8 s−1. The relaxation rates for the control group R2 = 10.8 ± 0.8 s−1 and the thalassemia group R2 = 14.3 ± 1.4 s−1 were significantly different (p (U-test) < 0.001) with no overlap. A weak Spearman rank correlation was found with LIC (RS = 0.71, p < 0.04), but not with plasma ferritin. Anterior pituitary height H and volume V were related by V [mm3] = 95 · H [mm] - 187 (R2 = 0.80). For the anterior pituitary, a significant correlation was found between R2 and volume (RS = −0.59, p < 0.04). Although volumes and heights did not significantly differentiate between the patients and controls, the two THAL patients with abnormal pituitary function had lower anterior pituitary volume and height compared with the two others with normal function. The one iron-overloaded SCD patient had normal R2 and pituitary function; volume and height were in the same range as controls. In summary, the higher transverse relaxation rates indicate elevated iron concentrations in the anterior pituitary gland in all of our thalassemia patients. Pituitary volumes or heights alone may reflect pituitary function, but abnormal volume/height was only seen in patients with high R2. Additional studies in patients with thalassemia and SCD are required to confirm these preliminary observations.

Acute Chest Syndrome (ACS) remains the leading cause of death and hospitalization in patients (pts) with sickle cell disease (SCD). There is limited data on the effects of ACS on lung function. From 1993 to 1997, 30 centers participated in the NACSG and prospectively analyzed 671 episodes of ACS in 538 pts. Pulmonary function tests (PFTs) included forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), forced expiratory flow during 25% to 75% of FVC (FEF 25–75), peak expiratory flow rate (PEF) and the ratio of FEV1/FVC. Data is reported as percent-predicted of normal values based on age and height. 128 pts (mean 16yrs, 4 to 52 yr range) had PFTs during an ACS episode (within a mean of 2.5 days of diagnosis) and then 12 weeks later. 94% of pts had abnormal lung volumes, defined as either FEV1 or FVC < 80%. Mean lung volumes during ACS and at follow-up are shown below. Table 1: Decreased Lung Volumes During ACS PFT During ACS Follow-up p-value FEV1 52% 79% Pts with abnormal lung volumes (FEV1 or FVC < 80%) and considered to have an obstructive pattern if the FEV1/FVC ratio was < to 85. Obstructive patterns in pts with abnormal lung volumes and the percent of pts who responded to bronchodilators (15% improvement in either FEV1 or FVC) are shown below. Table 2: Patterns of Abnormal Lung Volumes in SCD SCD Patients During ACS Follow-up Abnormal PFTs 94% 45% Obstructive Pattern 48% 46% Respond to bronchodilators 25% 8% In summary, ACS resulted in decreased pulmonary function in 94% of pts. It is striking that 49% pts had their PFTs reduced by half (FEV1 52% and FVC 55%). In pts with abnormal PFTs, 48% had evidence of obstruction and 25% of all pts tested improved with a bronchodilator. This is the first description of reversible abnormalities of pulmonary function occurring during ACS compared to baseline. An obstructive pattern is identified in a higher percentage of pts with SCD than in the local Oakland African American population (asthma prevalance 16%). While some pts PFTs improved with time, 45% remained abnormal at 12-week follow-up. ACS results in acute and chronic worsening of lung function. Future studies of ACS may reveal common pathogenic mechanisms with asthma, and lead to improved therapeutic interventions.

Avascular necrosis (AVN) of the hips affects half of sickle cell anemia (SCA) patients and can rapidly lead to total collapse of the hip. Treatment with supportive therapy alone is unsuccessful and results in half of all patients requiring hip surgery within 2 years of diagnosis. Prognosis in advanced cases is dismal, with surgery eventually required in all patients. Alternative therapies including aggressive physical therapy (PT) and hip coring decompression (HCD) may improve the natural history of AVN but neither have been evaluated prospectively in SCD. The goal of the prospective randomized National AVN Trial in SCA is to evaluate the safety of HCD and PT for AVN. 46 patients were randomized to have either HCD of their study hip followed by 6 weeks of an aggressive PT protocol, or to undergo only the PT protocol. Both treatment arms are balanced for Ficat stage and patient age. Outcome measures include clinical improvement as measured by the Children’s Hospital Oakland Hip Evaluation Scale (CHOHES), a 100 point validated scale that assesses hip function and pain associated with AVN in SCA. Additional measures include X-ray progression and the need for surgical intervention. This report presents hip survival rates in 39 study patients: 17 patients underwent HCD and 22 were treated in the PT arm. Average patient age was 26 (range 10 to 50). 67% had bilateral disease. The average follow-up is currently 40 months. In the survival graph, treatment failure was defined as additional hip surgery. 4 of the 39 study hips (10%) were treatment failures: 1/9 (11%) of Stage I, 3/19 (16%) of Stage II, and 0/11 (0%) of Stage III hips. Figure Figure In addition to a low treatment failure rate, hips in each Ficat stage show evidence of clinical improvement. CHOHES scores improved 17 points at 1 year and 22 points at 2 years; even Stage III shows a 20 point improvement at 1 year and 21 points at 2 years. Our data indicates that both HCD and aggressive PT are beneficial in the treatment of AVN in SCA. PT may be effective in the treatment of even fairly advanced Stage III AVN. The AVN Trial in SCA is ongoing; patients will be followed for 3 to 5 years, and a comparison of HCD to aggressive PT will be made upon completion.

Background: Sudden unexplained death is one of the leading causes of mortality in sickle cell disease (SCD). Prolonged QTc has been associated with sudden death in older patients and in those with cardiac disease. Sudden death due to cardiac arrhythmias occurs in thalassemia (Thal) patients from cardiac iron toxicity, and recently, QTc prolongation has also been identified in this transfusion-dependent population. Chronic transfusion and iron overload have become more frequent in patients with SCD due to treatment regimens aimed at stroke prevention and treatment of stroke, pulmonary hypertension (PH) and recurrent vaso-occlusive crisis. Cardiac iron toxicity is thought to be rare in SCD but other factors such as anemia, PH, and hemolysis-associated nitric oxide dysregulation may predispose SCD to prolongation of the QTc interval. The purpose of this study was to examine the prevalence of QTc prolongation in chronically transfused and iron-overloaded SCD (txSCD) patients compared to a control group of non-transfused SCD patients. Methods: In this study, electrocardiograms (EKGs) were reviewed from SCD patients participating in the MCSIO, a five-year prospective study of the complications of iron toxicity in SCD and Thal. Using Bazett’s formula, a subset of 96 EKGs were analyzed for QTc prolongation, defined as ≥ 0.45 seconds and borderline as 0.44 to 0.449 seconds. Echocardiograms (ECHOs) obtained within an average of seven months were analyzed for left ventricular dysfunction (LVD) --which was defined as an ejection fraction < 55% or shortening fraction < 28% --and the presence of PH, defined as a tricuspid regurgitant jet velocity (TRJV) of ≥ 2.5 m/second. Results: There was no difference in mean age (25.3 ± 13.6) or gender (64% female) between the 65 txSCD and 31 control SCD patients. The txSCD group had been transfused 10 ± 6.2 years and their baseline ferritin was 3107 compared to 116 in the controls. QTc prolongation was present in 32% of the txSCD and 29% of the control group (n.s.); borderline prolongation was seen in an additional 17% and 13%, respectively. Mean QTc in txSCD was also not significantly different from the SCD controls: 0.45±.04 vs. 43±.03 (n.s.). None of the 68 patients with ECHOs had LVD. 36 patients had TRJV measured during the study: 50% of the txSCD had PH compared to 30% of non-transfused SCD (n.s.). The average QTc in PH patients was 0.45 ± .04 compared to 0.43 ± .04 in those without PH (p=.09). However, the frequency of either prolonged or borderline QTc was significantly higher in patients with PH (72% vs. 22%, p= .007). No correlations between QTc and age, gender, or baseline laboratory values (hemoglobin, white blood count, or platelets) were found. In the txSCD, QTc was not correlated to ferritin or years of transfusion. Conclusions: Overall, QTc prolongation was found in 31 % of SCD patients and borderline prolongation in an additional 16%. QTc intervals ≥ 0.44 were more common in patients with PH. Transfusion exposure and iron overload were not associated with QTc prolongation in this group of txSCD patients. The frequency of QTc prolongation is concerning in SCD patients, who often have pulmonary hypertension and are treated with medications known to contribute to QTc prolongation. Routine screening for QTc prolongation appears warranted with treatment of high-risk SCD patients.