ALBERT

Description: Key Points The fraction of invariant NKT cells demonstrating activation is increased during painful crises compared with steady state. Regadenoson, an adenosine A2A receptor agonist, decreases the fraction of activated invariant NKT cells during painful crises.

Description: Abstract 2647 Rationale: Among children with sickle cell disease (SCD), a physician diagnosis of asthma has been associated with increased rates of acute chest syndrome (ACS), pain and mortality. Respiratory symptoms, including wheezing, occur in individuals with SCD independent of an asthma diagnosis. Few studies have evaluated the significance of asthma or respiratory symptoms in adults with SCD. Objective: The primary objective of this study was to determine whether adults with SCD and a physician-diagnosis of asthma have more ACS and pain episodes compared to adults with SCD but without asthma. A secondary objective was to evaluate the relationship between asthma-like symptoms and ACS and pain among adults with SCD. Methods: This was an observational cohort study of adults (≥ 19 years) with SCD who received care exclusively in the Washington University/Barnes Jewish Hospital system and completed baseline questionnaires including the ATS-DLD respiratory symptom survey. The questionnaires documented the frequency, severity and precipitants of symptoms such as wheezing, cough and shortness of breath. Enrollment into the study began August 2006. Hospitalizations for ACS and pain were determined from retrospective and prospective review of electronic medical records from January 1, 2004 to March 1, 2010 and analyzed using adjusted negative binomial regression models. Cox proportional hazards models were used to determine survival rates from date of consent through March 1, 2010. Spirometry was obtained from 69% of the study cohort. Results: Of 114 adults with SCD, those with a physician diagnosis of asthma (n=34) were more likely to have classic features of asthma including cough and wheeze, history of eczema, parental history of asthma, and an IgE level 〉150 kU/L (all p

Description: Primary hemorrhagic stroke is an uncommon but serious complication of sickle cell disease (SCD) with mortality from 20 to 65%. Proposed risk factors include previous ischemic stroke, aneurysms, low steady-state hemoglobin, high steady-state leukocyte count, acute chest syndrome, and transfusion. We performed a retrospective case-control study to evaluate risk factors for primary hemorrhagic stroke in adults (age 〉19 years) with SCD hospitalized at Johns Hopkins Hospital from January 1989 to June 2007. Cases had SCD and intraparenchymal (IPH), subarachnoid (SAH), or intraventricular (IVH) hemorrhage confirmed by neuroimaging or analysis of cerebrospinal fluid; traumatic subdural and epidural hemorrhages were excluded. Controls had SCD and ischemic stroke (focal neurological deficits with corresponding cerebral infarcts by neuroimaging). Both were identified by searching the hospital discharge database using ICD-9 codes for acute stroke and SCD and reviewing divisional records. We compared continuous variables by Student’s t-test and calculated odds ratios with exact methods. We identified 7 cases (mean age 31 years, range 19 – 49, 29% male) and 9 controls (mean age 37 years, range 21 – 61, 11% male). All cases had sickle cell anemia (HbSS) and 17% had a prior overt stroke; Controls had HbSS (5/9) and HbSC (4/9) and 50% had a history of overt stroke. Cases presented with impaired mental status (5/6), headache (7/7) and seizure (5/7). Controls presented with hemiparesis (7/8) and rarely seizure (1/7). Three cases had IPH involving the frontal lobe, frontal and parietal lobes, or basal ganglia. Four patients had SAH with IVH (2) and frontal IPH (1). Cerebral angiography identified aneurysms in 3 cases. One case (14%) and no controls died during the initial hospitalization. About 50% of cases (3/6) and controls (4/9) had elevated systolic blood pressure at the time of stroke. Cases had lower steady-state hemoglobin (mean ± SEM 7.4 ± 1 g/dl vs. 9.3 ± 1.1 g/dl), lower steady-state blood pressures (systolic 120 ± 7 vs. 132 ± 11 mm Hg, diastolic 72 ± 7 vs. 73 ± 5 mm Hg) and higher steady-state leukocyte counts (12,912 ± 1007/ul vs. 11,097 ± 2520/ul) than controls, but these differences were not statistically significant. Mean hemoglobin concentration at the time of stroke increased 1.3 g/dl (22%) from steady-state in cases and 0.7 g/dl (10%) in controls. Three cases had simple transfusions (1, 4, and 11 days before their primary hemorrhagic stroke) in preparation for surgery (2) and for aplastic crisis (1). No controls were transfused, but a woman with HbSS had a hemoglobin of 14.5 g/dl at the time of stroke (from excessive erythropoietin administration). In this group of adults with SCD, primary hemorrhagic stroke was associated with genotype and antecedent transfusion. Mortality was lower than that previously described and may reflect improvements in medical care or random variation within a small sample. The contribution of antecedent events and other potentially modifiable risk factors for hemorrhagic stroke in adults with SCD deserves further evaluation. Table 1: Associations with Primary Hemorrhagic Stroke Variable Odds Ratio (95% CI) P-Value NC indicates not calculated Genotype (HbSS vs. Other) NC (1.1-∝) 0.09 Seizure (at presentation) 20 (1.0–1059)

Description: Sickle cell disease (SCD) is characterized by widespread vaso-occlusion in venules that is initiated by the polymerization of deoxy-hemoglobin in sickle RBCs and exacerbated by leukocyte activation and endothelial injury. In the course of the disease, episodic flare-ups result in painful vaso-occlusive crises (pVOC) and acute chest syndrome that over time result in chronic tissue injury. We have previously shown that pVOC in SCD is associated with activation of a small subset of CD1d restricted T lymphocytes known as invariant NKT (iNKT) cells that release large amounts of pro-inflammatory cytokines and propagate an inflammatory cascade. Antigen presenting cells (APCs) stimulate the activation of iNKT cells by presenting lipid antigens on CD1d and by releasing co-activating cytokines such as IL-12 and IL-18. Cytokines released by activated iNKT cells such as IFN-γ further propagate inflammation by stimulating chemotaxis of and activation of additonal leukocytes. In mice, the cytokines that are released by activated iNKT cells trans-activate monocytes and neutrophils. In this study we investigated for the first time the effect of pVOC in patients on the activation of myeloid (CD11c+/CD123-) dendritic cells (DCs) (CD45+/Lin1-/HLA-DR+), monocytes (CD3-/CD19-/CD15-/CD66b-/CD14+), and neutrophils (CD3-/CD19-/CD15+/CD66b+). Our findings indicate that like iNKT cells, myeloid DCs, monocytes, and neutrophils are increased in peripheral blood of SCD subjects relative to non-SCD controls. Plasmacytoid DCs (CD11c-/CD123+) were little affected. This increase in cell numbers is enhanced during pVOC except for myeloid DCs which decrease, possibly due to extravasation out of the blood stream. In addition, CD1d+ myeloid DCs from SCD individuals express higher levels of the activation marker, CD86, and this is further increased during pVOC. Similarly, neutrophils and monocyte subsets including classical monocytes (CD14+/CD16-) and patrolling monocytes (CD14dim/CD16+) express higher levels of activated adhesion molecules, LFA-1 (detected with KIM127 antibody) and Mac-1 (detected with CBRM1/5 antibody that recognizes active CD11b), in SCD subjects during pVOC as compared to controls and steady-state SCD patients. Taken together, these findings strongly suggest that the severity of vaso-occlusion during the clinical course of SCD correlates with an increased pro-inflammatory state reflected by increased circulating activated leukocytes. These findings are also consistent with previous murine studies showing that iNKT cells are necessary, but not sufficient for initiating and amplification of tissue inflammation and damage. The activation of CD1d+ APCs during pVOC is likely to facilitate iNKT cell activation due to the expression of co-stimulatory molecules (CD86), inflammatory cytokines, and possibly lipid antigens. Moreover, the activation of adhesion molecules on monocytes and neutrophils may enhance their propensity to contribute to vaso-occlusion. Disclosures: Field: NKT Therapeutics: Consultancy.

Description: Patients with sickle cell disease have an increased number of circulating activated iNKT cells while murine SCD models report increased number and activation state of iNKT cells in target organs. Furthermore, the use of a murine iNKT cell-depleting antibody in murine SCD models prevents inflammation driven end-organ damage. NKTT120 is a humanized monoclonal antibody directed to the unique invariant TCR of iNKT cells that depletes these cells by ADCC. In preclinical studies, NKTT120 has demonstrated a safe and specific dose and time dependent depletion/recovery of iNKT cells. The preclinical efficacy and safety data supported a clinical development program to show that NKTT120 demonstrates the same safety and specificity for iNKT cell depletion from the peripheral circulation in SCD patients. In this first in human phase 1 dose-escalation study, we have examined the safety of NKTT120 in adults with steady state SCD. Future studies will explore the ability of NKTT120 prevent painful vaso-occlusive crises. Objective: To determine the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of NKTT120 in adults with steady state SCD. The optimal dose for a phase 2 study of NKTT120 will deplete iNKT for approximately 3 months allowing for periodic dosing. Methods: A first-in-humanphase 1 study utilizing a 3+3 design to evaluate single doses escalating over a range of 7 doses from 0.001 mg/kg to 1.0 mg/kg. The primary outcome measure is safety. Secondary outcomes include blood iNKT cell depletion and recovery, pain, analgesic use, quality of life (QoL), and pulmonary function. During a screening run-in period and after dosing of NKTT120, subjects maintained a daily smartphone eDiary (eSCaPe) to report pain, respiratory symptoms and analgesic use. ASCQ-Me and PROMIS QoL questionnaires were administered at clinic visits. The screening run-in outcomes will be used as baseline comparison for values obtained post-dosing. Results: A total of 21 patients were enrolled into the 7 cohorts of the completed and closed study. The drug was delivered as a 10-minute IV push in all cohorts. No MTD was defined, as no DLTs were reported. Three subjects each were dosed at 0.001, 0.003, 0.01, 0.03, 0.1, 0.3 or 1.0 mg/kg. At leastone month of follow-up data on circulating iNKT cell numbers are available for all of the patients dosed in the study. Only iNKT cell counts were affected by NKTT120 dosing, no change in other hematologic parameters was observed in peripheral blood. No acute elevation in circulating inflammatory cytokines was seen after antibody administration. All doses of NKTT120 resulted in maximum depletion of iNKT cells at the first time point (6 hours) monitored in all patients. During the recovery period, all patients had detectable iNKT cells in their peripheral blood. In all cohorts, the time to recovery of iNKT cells correlates with the starting circulating levels, with a longer recovery time for patients with lower baseline cell numbers. T1/2 is approximately 11 days. As observed in the pre-clinical safety studies, iNKT cell depletion and recovery was dose and time dependent. At the recommended Phase 2 dose (0.3 mg/kg) no iNKT cells were detectable in the peripheral circulation for a period of several months, suggesting near complete tissue depletion at these doses requiring recovery from T cell precursors that are not targeted by NKTT120. Conclusions: In adults with SCD,NKTT120 administered up to a dose of 1.0 mg/kg specifically reduces iNKT cells without NKTT120 dose limiting toxicity. Patients at the higher dose cohorts of NKTT120 illustrate temporal pattern for iNKT cell depletion and recovery in the circulation that inform the dosing strategy for phase 2 studies. The recommended Phase 2 dose is 0.3 mg/kg administered at a 3 month interval. The Phase 2 study will highlight the reduction of iNKT cells in the suppression of the inflammatory stimuli that promote many of the pathophysiologic sequelae seen in SCD. Disclosures Eaton: NKT Therapeutics: Employment. Mazanet:NKT Therapeutics: Consultancy, Equity Ownership. Nathan:NKT Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Description: An increased number of circulating activated iNKT cells have been reported in sickle cell disease patients, and in mouse studies, iNKT cells have been reported to have increased number and activation state in target organs. Depletion of iNKT cells in a mouse model of sickle cell disease decreases inflammation and prevents end-organ damage. NKTT 120 is a humanized monoclonal antibody directed against the iNKT cell invariant TCR that depletes these cells by antibody dependent cellular cytotoxicity. Preclinical studies show that NKTT120 has high affinity and specificity for iNKT cells. NKTT120 administration as a 10 minute IV infusion produces depletion and recovery of iNKT cells in a dose and time dependent manner. Our global hypothesis is that NKTT120 will deplete iNKT cells, reduce inflammation and prevent painful vaso-occlusive crises. In this phase 1 dose-escalation study, we have examined the safety of NKTT120 in adults with steady state SCD. Objective: To determine the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of NKTT120 in adults with steady state SCD. The optimal dose for a phase 2 study of NKTT120 will deplete iNKT for approximately 3 months allowing for periodic dosing. Methods: Phase 1 study utilizing a 3+3 design to evaluate single doses escalating over a range of 5 doses from 0.001 mg/kg to 0.3 mg/kg thus far. The primary outcome measure is safety. Secondary outcomes include blood iNKT cell number depletion and recovery, pain, analgesic use, quality of life (QoL), and pulmonary function. During a screening run-in period and after dosing of NKTT120, subjects maintained a daily smartphone eDiary (eSCaPe) to report pain, respiratory symptoms and analgesic use. ASCQ-Me and PROMIS QoL questionnaires were administered at clinic visits. The screening run-in outcomes will be used as baseline comparison for values obtained post-dosing. Results: At leastone month of follow-up data on iNKT cell numbers are available for the first eighteen patients dosed in the study. Three subjects were dosed at each dose level of 0.001, 0.003, 0.01, 0.03, and 0.1 and 0.3 mg/kg. Only iNKT cell counts were affected by NKTT120 dosing. No change in other hematologic parameters was observed. Eleven of 15 subjects in the first 5 cohorts had recovered iNKT cells by 28 days. Of the remaining 4 patients, 3 recovered iNKT cells by 56 days and the last recovered iNKT cells within 5 months. No patient has recovered iNKT cells in cohort 6 (0.3 mg/kg) within 28 days. Time to recovery of iNKT cells correlates with the starting circulating levels, with a longer recovery time for lower cell number. NKTT120 has been well tolerated with no dose limiting toxicities reported. Conclusions: In steady state adults with SCD,NKTT120 administered up to a dose of 0.3 mg/kg specifically reduces iNKT cells without NKTT120 dose limiting toxicity. Patient cohorts at higher doses of NKTT120 are planned to further define the most effective dose and dose interval for iNKT cell depletion and recovery in the blood and target tissues. The final dose selection will support longer term studies on the reduction of iNKT cells in the suppression of the inflammatory stimuli that promote many of the pathophysiologic sequelae seen in SCD. Disclosures Vichinsky: ApoPharma: Research Funding; ARUP Research labs: Research Funding. Eaton:NKT Therapeutics: Employment. Mazanet:NKT Therapeutics: Employment.

Description: Background: For research purposes, painful crises in sickle cell disease (SCD) have either been self-defined by patients, or adjudicated by research experts, most often based on whether urgent care or hospital care was sought for pain related to SCD. The Pain in Sickle Cell Epidemiology Study (PiSCES) determined that three-fourths of self-defined crises days were not managed in urgent or hospital care. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (AAPT) published a taxonomy of chronic SCD pain, defined as pain on most days of 6 months duration, along with at least one clinical sign, and no better explanation for the pain. We served on a similar SCD consensus panel to propose a more expansive taxonomy of acute sickle cell pain or painful episodes, informed by the PiSCES dataset (manuscript under review). Here we present three PiSCES-derived definitions of acute painful episodes, and we analyze the impact of various definitions on pain outcome results potentially useful for research. Methods: PiSCES Patients (N=81) who completed at least 5 out of the expected 6 months of daily diaries and did not have gaps in their daily diary of 4 days or more were included. Patients self-reported their worst sickle cell pain intensity on a scale from 0 (none) to 9 (unbearable), and independently self-reported whether they were having a crisis that day, whether they went for an unscheduled physician visit, an Emergency Department visit, or whether they were hospitalized for sickle cell pain. Definitions of acute pain episodes compared here include self-reported crisis days, days with pain ≥ 5, and days with utilization of the ED or overnight hospitalization (other potential definitions not shown). To meet any definition, a crisis day (pain≥ 5, utilization) had to be reported for 2 or more consecutive days. Non-crisis intervals were 2 or more consecutive days without a self-reported crisis (pain ≥ 5, utilization). The average length of non-crisis intervals was considered to represent the time between crisis episodes. For

Description: Background: Patients with sickle cell disease (SCD) suffer from frequent vaso-occlusive crises (VOC), the leading cause of hospitalization and ED visits for these patients. Infusion centers (IC) are alternatives to ED care and may provide patients with a better care experience. We previously demonstrated in a single center that the use of such centers provides more rapid pain control and can decrease the risk of a hospital admission. For the management of VOC the NHLBI's guidelines recommend that patients receive analgesic therapy within 60 minutes of registration and that pain be reassessed every 15-30 minutes until it is controlled. In the ESCAPED study, we aimed to learn whether the ED or IC more rapidly provides analgesia to patients who present with an uncomplicated VOC. Methods: The ESCAPED study is a prospective cohort study that recruited subjects at four sites (Baltimore, Cleveland, Milwaukee and Baton Rouge). The Baltimore and Milwaukee sites have dedicated ICs that treat only adults with SCD; the Cleveland and Baton Rouge sites have ICs that treat a diverse group of patients requiring infusion services. Patients were enrolled during regular outpatient visits between 4/2015 and 12/2016. Uncomplicated crisis was defined as an acute episode of pain with no known other cause and required treatment with parenteral pain medications. Upon study entry, participants completed surveys to collect demographic data; chart abstraction was done for information on comorbidities. Data was extracted after the acute visits for the primary endpoint: time to first dose of pain medication. We also extracted data on reassessment of pain after the first dose of parenteral pain medication and admission or discharge status. Patients' comorbidities were updated through chart abstraction after each visit. Each participant was followed for 18 months and data from visits for acute, uncomplicated VOC were collected. All acute visits were recorded and complete data was collected for each patient from the first visit each month to each site of care for uncomplicated crisis. Time-varying propensity scores estimated by a random effects model was used to balance covariates in the two arms. The treatment effects were estimated using a sub-classification approach and standard errors were computed by nonparametric bootstrapping at the individual level. Results: 483 subjects were enrolled and 444 completed 18 months of follow up (29 withdrew, 10 died). The median follow-up was 8.2 months (IQR, 5.7-12.0) for the 39 subjects who did not complete the study. There were 4851 acute visits for uncomplicated VOC of which 2910 had the complete data collected. 1445 visits to an ED and 1465 visits to an IC. The mean number of visits per patient was 10.0 (SD, 15.5) and median number was 4 (IQR, 1-12.5). 115 subjects had no acute visits during the study period. In the adjusted analyses, the mean time to first dose of parenteral pain medications was 125 minutes in an ED setting and 63 minutes in an IC setting (95% CI, 54-69). Patients seen in an IC were significantly more likely to have their pain reassessed 30 minutes after their first dose of pain medication than patients treated in an ED (OR, 2.5; 95% CI, 2.1-3.0) and visits to the ED were significantly more likely to end in the patient being admitted than visits to the IC (OR, 5.9; 95% CI, 4.7-7.3). Conclusions: With adjustment for differences between patients treated in the ED and IC, we demonstrated that those treated in an IC have significantly better treatment experiences than subjects treated in an ED: a 50% reduction in time to first dose of pain medication and an almost 6-fold decrease in hospital admission. Increasing access to infusion clinics is essential to improving the quality of care of uncomplicated VOC in adults with SCD. Disclosures Lanzkron: GBT: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Prolong: Research Funding; NHLBI: Research Funding; PCORI: Research Funding; Selexys: Research Funding; Ironwood: Research Funding. Little:Doris Duke Charitable Foundations: Research Funding; PCORI: Research Funding; Hemex: Patents & Royalties: Patent, no honoraria; NHLBI: Research Funding. Field:Incyte: Research Funding; Ironwood: Consultancy, Research Funding; Prolong: Research Funding. Haywood:PCORI: Research Funding. Varadhan:PCORI: Research Funding. Saheed:PCORI: Research Funding. Proudford:PCORI: Research Funding. Robertson:PCORI: Research Funding. Kincaid:PCORI: Research Funding. Burgess:PCORI: Research Funding. Green:PCORI: Research Funding. Wang:PCORI: Research Funding. Seufert:PCORI: Research Funding. Brooks:PCORI: Research Funding. Piehet:PCORI: Research Funding. Griffin:PCORI: Research Funding. Arnold:PCORI: Research Funding. Frymark:PCORI: Research Funding. Huang:PCORI: Research Funding. Wallace:PCORI: Research Funding. Segal:PCORI: Research Funding.

Description: Background: Warm antibody autoimmune hemolytic anemia (wAIHA) is a rare and often serious disease characterized by antibody-mediated destruction of red blood cells (RBCs). Activation of Fc receptors on macrophages in turn activates spleen tyrosine kinase (SYK), which triggers a signaling cascade leading to phagocytosis of the antibody-bearing cells. Fostamatinib, a SYK inhibitor, markedly improved Hgb levels in 9 of 17 (53%) patients with wAIHA during a phase 2, open-label, multicenter study. This abstract reports the results of ongoing fostamatinib treatment as of 2 July 2018 in patients who completed the 24-week treatment period and rolled over into the extension period of the study. Methods: Eligible adult patients had primary or secondary wAIHA and had failed more than one prior treatment for wAIHA. Patients had to have hemoglobin (Hgb) 10 g/dL with an increase of ≥2 g/dL from baseline by Week 24 without rescue therapy or RBC transfusion) OR have shown a beneficial trend during the 24-week treatment period and [2] tolerated study drug. Fostamatinib 150mg BID (or the dose taken at the end of the 24-week treatment period, if a dose reduction had occurred) was taken orally with no food restriction, and patients were seen every 6 weeks during the extension period. Results: Six patients have entered the extension period including 5 who had met the primary efficacy endpoint and 1 who showed a beneficial trend at Week 24 (and had a response at Week 30). One patient had lymphoproliferative disease. Prior AIHA treatment included splenectomy (1), steroids (6), and rituximab (2). The median duration of disease was 1.9 years (range 0.4-15.7). The mean age was 58.7 years (range 30-86), 5 were female, all were white, and 4 were Hispanic or Latino. At baseline the median Hgb was 9.1 g/dL (range: 8.6-9.5); the median lactate dehydrogenase was 273 U/L (range 233-781); the median reticulocyte count was 252.2 x109/L (range 7.8-350.0); and the median haptoglobin was 7.0 mg/dL (range 7.0-9.0). The direct antiglobulin test was positive for IgG in 5 patients at screening. Median Hgb levels increased over the course of the study. See figure. Four of 6 patients had an ongoing response as of the data cutoff date, and none has had rescue therapy or an RBC transfusion. All 6 patients had ≥1 adverse event (AE) during the study, including noninfectious diarrhea in 1 (treatment-related), hepatic disorders in 3 (treatment-related in 2; treatment interrupted in 1), and hypertension in 1 (not related). One patient had a serious AE (inappropriate antidiuretic hormone secretion), which was not related to fostamatinib. To date, no new safety signals have been detected. Summary/Conclusion: Patients with wAIHA continued to display markedly improved Hgb levels during the extension period of the study. Side effects were manageable and consistent with those previously reported with fostamatinib in other conditions. Figure. Figure. Disclosures Kuter: ONO: Consultancy; Protalex: Research Funding; Rigel: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Consultancy; Novartis: Consultancy; Amgen Inc.: Consultancy; Principia: Research Funding; Bioverativ: Consultancy, Research Funding; Argenx: Consultancy; Syntimmune: Consultancy; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Arnold:Amgen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; UCB: Consultancy; UCB: Consultancy; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding. Boxer:Incyte: Speakers Bureau; Rigel: Speakers Bureau; AbbVie: Speakers Bureau. Broome:Bioverativ: Honoraria; Alexion: Honoraria. Field:Prolong: Research Funding; Ironwood: Consultancy, Research Funding; Incyte: Research Funding. Lowe:Rigel: Consultancy. Tong:Rigel: Employment, Equity Ownership. Zayed:Rigel: Employment, Equity Ownership. Duliege:Rigel: Employment, Equity Ownership.

Description: Background: Chronic transfusion therapy (CTT) is a mainstay of prophylactic management and treatment for adults and children with high risk Sickle Cell Disease (SCD). We estimate that 10-20% of all adults with SCD managed at our centers, especially those with homozygous HbSS disease, are on CTT, for long-term management of cerebral vasculopathy, significant end organ damage, or chronic pain. Iron overload is a common complication of CTT and for patients receiving intermittent transfusion to treat acute complications. Each unit of transfused blood introduces approximately 250 mg of iron into the bloodstream, and with it, increased oxidative stress (A. Remacha, et al., "Guidelines on haemovigilance of post-transfusional iron overload," Blood Transfusion, vol. 11, no. 1, pp. 128-139, 2013). High iron levels in the blood cumulatively lead to systemic iron deposition, particularly in the liver and heart, and untreated may lead to organ dysfunction or death. Patients with high iron levels should be put on iron chelation. Recent NHLBI guidelines suggest that patients on CTT be monitored for iron accumulation with quarterly ferritin levels, and annual or semiannual liver iron scans to assess hepatic iron burden, though the optimal frequency of these scans has not been established (B. P. Yawn, et al., "Management of Sickle Cell Disease: Summary of the 2014 Evidence-Based Report by Expert Panel Members," JAMA, vol. 10, no. 312, pp. 1033-1048, 2014). We examined iron overload, its frequency, severity, and management, in a modern population of adults with SCD enrolled in the multi-center prospective sickle cell registry, Globin Research Network of Data and Discovery (GRNDaD). Methods: GRNDaD is a multi-site registry of both adult and pediatric SCD patients, currently accruing at 5 urban sickle cell centers, in Baltimore MD, Cleveland OH, Milwaukee WI, Columbus OH, and Oakland CA. It currently contains prospective baseline and annual update information on nearly 500 people with SCD. Additionally, approximately 150 more patients have consented, with data entry pending. The dataset comprises demographics as well as baseline and yearly lab values, complications, procedures, treatment, and vaccination history for each patient. Among these data are ferritin levels, liver iron scan results, and chelation therapy information. We analyzed ferritin levels in people with SCD, relative to genotype, age, gender, treatment type, liver iron scan results, and chelation therapy history. Results: There were 402 adults (age≥18 years) in GRNDaD who had a non-crisis ferritin level from a routine follow-up visit. This included people with phenotypic homozygous SCD (HbSS, n=255 and Sβ0 thalassemia, N=13), variant SCD (HbSC, n=80, or Sβ+ thalassemia, n=37), and other or unknown genotypes (n=17, Table 1). Nearly 3 in 10 of all patients with SCD (n=118, 29.3%) had a ferritin level at baseline ≥1500 mg/dL, which is an accepted threshold above which to initiate chelation. Most people with an elevated ferritin had phenotypic SCA (homozygous Hb S) (n=111, or 94%). Over half of all SCD patients with a critically elevated ferritin were on CTT (n=64, 54%), and a similar number of people with SCD and critical ferritin levels were on chelation (n=64, 54%). Less than 1 in 4 had had a liver iron scan within 3 years (n=27, 23%). More than 1 in 3 patients with critical ferritin levels and no chelation therapy remained on CTT (n=21, not shown). Conclusions: Our multi-site registry, GRNDaD, prospectively surveyed a sizable population of adults with SCD, including data about iron overload. Of the adults in the GRNDaD registry with iron overload, we identified an unacceptably high fraction, nearly half, who were not on chelation. Most of these patients were people with phenotypic homozygous SCD. We are systematically addressing this deficiency with educational tools through GRNDaD. Since GRNDaD sites are academic centers across the country which focus on the management of SCD, we speculate that the problem of undertreated iron overload nationally is probably both widespread and under-recognized. We anticipate that, as GRNDaD continues to add additional sites, it will evolve as a robust resource through which to highlight important opportunities for clinical quality improvement in the expanding young adult population with SCD. GRNDaD may be a model for identifying and addressing deficiencies in current clinical practices for management of SCD. Disclosures Lanzkron: selexys: Research Funding; Ironwood: Research Funding; PCORI: Research Funding; HRSA: Research Funding; Pfizer: Research Funding; NHLBI: Research Funding; GBT: Research Funding; Prolong: Research Funding. Field:Incyte: Research Funding; Prolong: Research Funding; Ironwood: Consultancy, Research Funding. Desai:University of Pittsburgh: Research Funding; Selexy/Novartis: Research Funding; NIH: Research Funding; Ironwood: Other: Adjudication Committee; FDA: Research Funding; Pfizer: Research Funding. Little:PCORI: Research Funding; NHLBI: Research Funding; Hemex: Patents & Royalties: Patent, no honoraria; Doris Duke Charitable Foundations: Research Funding.