ALBERT

Description: Background β-globin gene transfer into hematopoietic stem cells (HSCs) could reduce or eliminate sickle cell disease (SCD)-related manifestations. LentiGlobin for SCD gene therapy contains autologous CD34+ cells transduced with the BB305 lentiviral vector (LVV), encoding a human β-globin gene with the anti-sickling T87Q mutation (βA-T87Q). The safety and efficacy of LentiGlobin for SCD is being evaluated in the ongoing Phase 1/2 HGB-206 Study (NCT02140554). The initial 7 patients (Group A) were treated with LentiGlobin made from bone marrow harvested HSCs. The protocol was modified to improve HbAT87Q production by including pre-harvest red blood cell (RBC) transfusions, increasing the total busulfan exposure, and using a refined LentiGlobin manufacturing process (Group B, n=2). An additional modification was made for Group C patients where HSC collection by plerixafor mobilization followed by apheresis was instituted. Data from these Group C patients are discussed here. Results from patients in Groups A and B are reported separately. Methods Patients (≥ 18 years) with severe SCD (including those with recurrent vaso-occlusive crisis [VOC] and acute chest syndrome [ACS]) were screened for eligibility. Patients received 240 µg/kg of plerixafor 4-6 hours prior to HSC collection via apheresis. CD34+ cells were transduced with BB305 LVV. Patients underwent myeloablative busulfan conditioning and subsequent LentiGlobin drug product (DP) infusion. Patients were monitored for adverse events (AEs), engraftment, vector copy number (VCN), total hemoglobin (Hb) and HbAT87Q expression, hemolysis markers, and SCD clinical manifestations. Data are presented as median (min-max). Results: As of 7 March 2019, 19 Group C patients, aged 26 (18-36) years, had initiated mobilization/apheresis and 13 patients were treated with LentiGlobin for SCD gene therapy. Median DP VCN, % transduced cells, and CD34+ cell dose in the 13 treated patients were: 3.8 (2.8-5.6) copies/diploid genome (c/dg), 80 (71-88) %, and 4.5 (3.0-8.0) x 106 CD34+ cells/kg, respectively. The median follow-up was 9.0 (1.0-15.2) months. Twelve patients achieved neutrophil and platelet engraftments at a median of 19 (15-24) days and 28 (19-136) days, respectively. As of the data cut-off, engraftment was not yet evaluable in 1 patient at 1-month post-infusion. All patients stopped red blood cell (RBC) transfusions within about 3 months post-LentiGlobin gene therapy. Median total hemoglobin (Hb) and Hb fractions in patients at various time points are shown in Figure 1. Median HbS levels were at or below 50% in all patients with at least 6 months follow-up. The median total Hb at last visit in 8 patients with at least 6 months of follow-up, was 11.5 (10.2-15.0) g/dL, with a corresponding HbAT87Q median contribution of 5.3 (4.5-8.8) g/dL and a median HbS 5.7 (4.8-8.0) g/dL. Of these 8 patients, 6 had a history of VOCs or ACS. The median annualized VOC+ACS rate in these patients was 5.3 (3-14) pre-treatment and decreased to 0 (0-2) post-treatment. One Grade 2 VOC was observed 3.5 months post-treatment. No ACS or serious VOCs were observed in Group C patients' post- treatment. Lactate dehydrogenase, reticulocyte count, and total bilirubin at last visit post-LentiGlobin infusion were 225.0 (130.0-337.0) U/L, 150.0 (42.1-283.0) 109/L, 22.2 (3.42-39.3) µmol/L, respectively, trending towards normalization. The most common non-hematologic Grade ≥ 3 AEs were febrile neutropenia (n=10) and stomatitis (n=7) post-DP infusion. Serious AEs were reported in 6 patients post-LentiGlobin treatment, most common being nausea and vomiting. To date, there have been no DP-related AEs or graft failure, vector-mediated replication competent lentivirus detected, or clonal dominance reported. Longer follow-up and additional patient data will be presented. Summary The safety profile of LentiGlobin gene therapy for SCD remains consistent with single-agent busulfan conditioning and underlying disease. Patients in HGB-206 Group C experienced high-level, sustained expression of gene-therapy derived hemoglobin, with median HbS levels reduced to ~50% and median total Hb levels of 11.5 g/dL at 6 months. The cessation of clinical complications (no ACS or serious VOCs) and decreased hemolysis suggest a strong therapeutic effect after LentiGlobin gene therapy in patients with SCD. Disclosures Kanter: Peerview: Honoraria; NHLBI: Membership on an entity's Board of Directors or advisory committees; Rockpointe: Honoraria; SCDAA: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Imara: Consultancy; Jeffries: Consultancy; Modus: Consultancy; Guidepoint Global: Consultancy; GLG: Consultancy; Cowen: Consultancy; bluebird bio, Inc: Consultancy; Medscape: Honoraria; Sangamo: Consultancy. Kwiatkowski:Terumo: Research Funding; Novartis: Research Funding; Apopharma: Research Funding; Imara: Consultancy; Celgene: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy. Schmidt:German Cancer Research Center, Heidelberg, Germany: Employment; GeneWerk GmbH, Heidelberg, Gemrany: Equity Ownership. Miller:bluebird bio, Inc.: Employment, Equity Ownership. Pierciey:bluebird bio, Inc.: Employment, Equity Ownership. Huang:bluebird bio, Inc.: Employment, Equity Ownership. Ribeil:bluebird bio, Inc.: Employment, Equity Ownership. Thompson:Baxalta: Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; bluebird bio, Inc.: Consultancy, Research Funding. Walters:AllCells, Inc: Consultancy; TruCode: Consultancy; Editas Medicine: Consultancy.

Description: Introduction: Allogeneic hematopoietic cell transplantation (HCT) is curative therapy for sickle cell disease (SCD). Good outcomes have spurred an increase in the use of HCT for SCD, including an increasing number of trials using alternative donors. As survival improves, assessment of long-term outcomes and potential late effects (LEs) in this patient population is critical. We evaluated the data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) to study incidence and risk factors for LEs following HCT for SCD. Methods: Patients reported to the CIBMTR with a diagnosis of SCD who had undergone their first HCT between 1996 and June 2015 were included in this analysis. Patients with graft failure were excluded. We performed a descriptive analysis of patient, disease, donor, and transplant-related factors. The cumulative incidence (CI) of LEs was estimated at 1, 3, and 7 years post-HCT. The number of pre- versus post-HCT SCD-specific disease complications was computed. Overall survival (OS) probabilities were calculated using the Kaplan-Meier method. Multivariable Cox regression analysis was used to evaluate risk factors related to OS and LEs. Results: The study population consisted of 355 patients. The median age at HCT was 10 years (range 15 years of age was associated with significantly inferior OS (mortality HR 7.26, 95% CI 3.57-14.77). Multivariable analysis for LEs demonstrated an increased risk of diabetes (HR 7.29, 95% CI 2.94-18.08) and pulmonary abnormalities (HR 5.90, 95% CI 1.14-30.42) with unrelated donor, while older age at HCT was associated with avascular necrosis (HR 14.19, 95% CI 1.86-108.47), diabetes (HR 3.45, 95% CI 1.69-7.05), and congestive heart failure (HR 8.02, 95% CI 1.13-56.94). SCD-related symptoms overall decreased from pre- to post-HCT (Table 1), most notably acute chest syndrome, vaso-occlusive pain crises, and stroke. Conclusions: Patients with SCD who have undergone HCT for SCD in recent years have excellent OS, confirmed in this CIBMTR multicenter dataset, with diminished SCD-related symptom burden post-HCT. However, they remain at-risk for a myriad of LEs, with risk factors including older age at HCT and unrelated donor, necessitating systemic organ-based follow up post-HCT. Continued follow-up of this patient population is critical to provide appropriate counseling for medical providers, patients, and families considering HCT as a treatment option for SCD. Disclosures Shaw: Therakos: Other: Speaker Engagement.

Description: Abstract 3240 The role of pulmonary hypertension as a common and attributable cause of mortality in patients with sickle cell disease remains controversial. To assess this question and explore risk factors for death in patients with sickle cell disease we evaluated 632 patients in the Walk-PHASST pulmonary hypertension screening cohort, recruited from nine different study sites in the United States and one site in the United Kingdom. Methods: Patient characteristics and their associations with mortality were analyzed with Cox proportional hazards regression analysis. Based on data from three right heart catheterization screenings studies that have recently been published, we defined the presence of pulmonary hypertension for this analysis by a Doppler-echocardiographic measurement of the tricuspid regurgitant jet velocity (TRV) ≥ 3.0 m/s, which has a 67–75% positive predictive value for a mean pulmonary artery pressure ≥ 25 mm Hg by right heart catheterization. This therefore represents a very conservative threshold for a large population screening study. Among subjects with a measurable TRV (n=572), 64 (11.2%) had measurements of ≥ 3.0 m/sec. Among those with measurable NT-proBNP (n=582), 140 (24.1%) had measurements ≥160 pg/mL, a value associated with both pulmonary hypertension and mortality. A total of 39 (7.4%) had both high TRV (≥3.0 m/sec) and high NT-proBNP (≥160 pg/mL). Results: Over a median follow-up time of 29 months, we observed 22 deaths. 50% (N=11) of these patients had a TRV≥ 3.0 m/sec. At 24 months the cumulative survival was 83% for patients with TRV ≥ 3.0 m/sec and 98% for patients with TRV 〈 3.0 m/sec (p

Description: Introduction: The pan-selectin antagonist rivipansel (GMI-1070) reduced intravascular arrest of red/white blood cell aggregates and improved blood flow and survival in a mouse model of sickle cell disease vaso-occlusive crisis (SCD VOC). In a Phase 1 study of GMI-1070 infusion in SCD adults at steady state (not in VOC), GMI-1070 decreased markers of cellular activation including neutrophil integrins, platelet/neutrophil aggregates, soluble adhesion molecule concentration; and markers of hemostatic activation. Furthermore, in a randomized Phase 2 study of SCD patients, treatment of VOC with GMI-1070 improved clinical outcomes such as time to resolution of crisis, time to discharge, and IV opioid use. Herein we report on the effect of GMI-1070 on biomarkers of cellular and hemostatic cascade activation from this Phase 2 trial. Methods: Patients in VOC enrolled in a prospective, randomized multi-center double-blind Phase 2 trial, ages 12-60 with HbSS or HbSB0thalassemia were treated with GMI-1070 q12h or placebo, in addition to standard treatment per institutional practice, until resolution of VOC. Clinical outcomes and pharmacokinetics have been previously reported (ASH 2013 Abstracts 775, 776, and 2206). Biomarker blood samples were drawn prior to study drug, and on a sparse sampling basis at times starting 30 minutes after initial dose and continuing until 36 hours after the last dose. Analytes measured included: soluble adhesion molecules E-selectin (sEsel), P-selectin, L-selectin, intercellular adhesion molecules 1 and 3, vascular cell adhesion molecule-1; and tissue factor and thrombin-antithrombin complexes by ELISA. At some sites, surface expression of monocyte b2 integrins MAC-1 & LFA-1 and platelet-monocyte aggregates were also measured by flow cytometry. Comparisons were made between the GMI-1070 and placebo groups, and serial expression levels were compared over time. Subgroup analyses were performed by hydroxyurea (HU) use, age group, baseline WBC, and responders' based on clinical outcomes. A mixed effect model was used to test the LS means difference at each time point and ANCOVA model was used to analyze the nadir, peak, and last dose values. Results: ELISA and flow cytometry samples were collected from 70 and 15 subjects, respectively. Soluble E-selectin levels were reduced for the group on GMI-1070 compared to placebo throughout hospitalization, and the differences were statistically significant at some time-points (Figure 1). Baseline sEsel levels were similar; but the peak, nadir, and level at last dose were all lower in the GMI-1070 group (Figure 2). Exploratory subgroup analysis by HU use, age group, response as measured by visual analog scale or opiate use, frequency of VOC in the past, and baseline white blood cell count revealed consistently lower sEsel levels in the GMI-1070 group. Many, but not all, of these differences reached statistical significance. Conclusion: GMI-1070 use during VOC resulted in consistent and significant reductions of sEsel, overall and in sub-groups as compared to placebo. These findings are consistent with the hypothesized effect of GMI-1070 on endothelial activation and/or apoptosis, mediated by inhibition of E-selectin, although an effect on sEsel clearance cannot be excluded. A Phase 3 study is planned to evaluate efficacy and safety of GMI-1070 as treatment for VOC. Soluble E-selectin concentrations may be useful as a biomarker of pharmacodynamic effect. Figure 1: sE-sel was reduced in the GMI-1070 group at all timepoints tested. Comparison to placebo for change from baseline over time is shown. *p

Description: Background Depression and catastrophizing are critically important variables in understanding the experience of pain in patients with several types of chronic pain. In the PiSCES study, negative correlations were observed between high catastrophizing scores with greater depression and lower quality of life in adult patients with sickle cell disease (SCD). These psychological covariates have not been studied extensively in pediatric patients with SCD. Methods Patients entering a study of quantitative sensory testing (QST) completed baseline psychological covariates which included PROMIS measures of pain intensity, interference, anxiety, depression, sleep, fatigue and peer relationships. Participants also completed the Pain Catastrophizing Scale (PCS-child version, ©Sullivan MJ), Child Somatization Inventory (Walker L et al), Pediatric Pain Coping Inventory*(Varni JW et al) as well as Peds QL Generic*(Varni JW et al) and SCD specific*(Panepinto JA et al) measures of Quality of life. We performed a correlational analysis on psychological covariates with quality of life. Results A total of 24 patients were included in the study, however depression scores were missing in 2 patients and catastrophizing scores were missing in one patient.14 patients (58.3 %) had HbSS, 7 patients (29.1%) had HbSC and 3 patients (12.5%) had HbS-beta+ thalassemia. In the past 3 years prior to the study patients with HbSS experienced a median of 4 (IQR: 3-5), HbSC a median of 3(IQR: 0-9) and HbS-beta+thal a median of 7 (IQR: 3-13) vaso-occlusive crises (VOC). The median hemoglobin level was 10.4 (IQR: 8.8-11.1) for patients with HbSS, 13.3 (IQR: 11.3-13.5) for patients with HbSC and 12.2 (IQR: 11.6-13.3) for patients with HbS-beta+ thalassemia. The median score on the Pain Catastrophizing scale was 29 (IQR: 13-35). The median total score on the Peds QL generic QoL scale was 74.4 (IQR: 57.05-87.01) and the SCD specific QoL was 61.9 (IQR: 50.65-77). The median depression score was 44.35 (IQR: 31.8-53.8) and median anxiety score was 46.15 (IQR: 35-51.8). There was a significant negative correlation between catastrophizing on PCS and the total Peds QL SCD specific (Spearman’s rho= -0.57, p= 0.0043) and generic (Spearman’s rho= -0.41, p=0.047) quality of life scores. A similar significantly negative correlation was seen between the catastrophizing dimension score on the Pediatric Pain Coping Inventory with total scores on the Peds QL SCD specific (Spearman’s rho= -0.65, p=0.0006) and generic (Spearman’s rho= -0.59, p=0.002) quality of life scores. There was also a significant negative correlation between depression (on the PROMIS depression module) with SCD specific (Spearman’s rho= -0.58, p= 0.0046) and generic (Spearman’s rho=-0.71, p=0.0002) quality of life scores. There was no correlation between catastrophizing (PedsQL Pediatric Pain Coping Inventory- Catastrophizing dimension or Pain Catastrophizing Scale) and healthcare utilization as measured by VOC requiring Emergency room visit or hospital admission over a 6 month, one year or three year period. Conclusions Children with SCD have a high median catastrophizing score. Catastrophizing and depression scales have a significant negative correlation with quality of life scores. Thus, pain, depression, and catastrophizing might all be important therapeutic targets in the comprehensive management of SCD in children. *PedsQL™ contact information and permission to use: Mapi Research Trust, Lyon, France. E-mail: PROinformation@mapi-trust.org – Internet: www.Mapi-trust.org andhttp://www.pedsql.org/index.html Disclosures: No relevant conflicts of interest to declare.

Description: Background Pain is the hallmark of sickle cell disease (SCD) but burden of pain is underestimated when measured using health care visits for vaso-occlusive crisis. In the PiSCES study adult patients reported pain on 〉 50% of diary days but sought care on only 3.5 % of diary days. Accurate assessment of the burden of pain and related morbidity is crucial in clinical care and research studies in SCD. Paper based pain diaries for assessing daily pain are limited by recall bias, errors, inflated retrospective reports and falsely high compliance due to backfilling of entries. Electronic pain diaries facilitate real-time data capture, are convenient, prevent backfilling, maximize compliance and facilitate data management. They have been used in children with arthritis, cancer, abdominal and musculoskeletal pain but no validated instrument is available for use in children with SCD. Objective To develop, establish the face and content validity, and usability of a novel web-based multidimensional electronic pain diary for children and adolescents with SCD. Methods Needs assessment: Pediatric subjects in a pilot SCD pain intensity diary study participated in qualitative interviews to assess their preferences regarding an electronic pain diary. Instrument development: Items for the pain diary were adapted for SCD from “e-Ouch”(c), an electronic pain diary validated for use in children with arthritis. Items assess pain intensity, duration, interference with daily tasks, sleep, fatigue, precipitating factors, pain relieving treatments and response to treatments using the Numerical Rating Scale (0-10). We created a web-based pain diary that can be accessed via a secure website using a smartphone or computer. Face validity: Experts in SCD, pain and psychometrics rated the items on a 5 point Likert scale for content, language, clinical relevance, comprehensiveness of answer choices and likely feasibility and acceptability in children with SCD. Two iterative cycles of expert review were conducted and were used for modification of items. Content validity: Using items with established face validity, two iterative cycles of testing (n=5 each) with paper screenshots of questions using semi-structured cognitive interviewing techniques were done in pediatric patients age 15-22 with SCD. Preliminary usability testing: Participants age 9-21(n=5) pilot tested the web-based electronic pain diary on a computer, smartphone and tablet. They were asked to recall their current pain and pain in the prior 12 hours while answering the diary questions. The usability testing was followed by semi-structured interviews. Results Needs assessment: Patients indicated that electronic monitoring of pain could facilitate coordination of care, communication with providers and early intervention and that twice daily electronic documentation of pain would not pose an unacceptable burden. Face validity: Items were reviewed by 15 experts in the first iterative cycle and 12 experts in the second iterative cycle and were modified for language, content and relevance; 2 items were deleted and 1 item was added. Content Validity: During the first iterative cycle, participants identified items that were difficult to understand, ambiguous or irrelevant. Number of items was reduced from 18 to 13. During the second iterative cycle, one repetitive item was removed and others minimally modified. To minimize user burden items were redistributed so pain intensity, location, quality and precipitating factors were asked twice daily; effect of pain on sleep was asked in the morning and pain interference with daily activities, mood, school and interactions and clinical management items were asked in the evening. Usability testing: Participants were easily able to navigate between questions, use the 0-10 NRS slider, select affected areas on the body image and select checkbox options and provided positive feedback on the question content and, layout of the diary, ease of its use and preference for accessing it from a smartphone. Conclusions This study established the face and content validity and usability of a web-based multidimensional electronic pain diary developed for use in children with SCD. This instrument can be used to assess pain as a patient reported outcome in clinical trials, to enhance communication in clinical care and as a comprehensive measure of pain phenotype in mechanistic studies. Disclosures: No relevant conflicts of interest to declare.

Description: Background LentiGlobin for SCD gene therapy contains autologous CD34+ hematopoietic stem cells (HSCs) transduced with the BB305 lentiviral vector (LVV) encoding β-globin with an anti-sickling substitution (T87Q). Its safety and efficacy are being studied in the ongoing multi-center Phase 1/2 HGB-206 trial (NCT02140554). Initial patients received LentiGlobin drug product (DP) using bone marrow-harvested (BMH) CD34+ HSCs transduced with the BB305 LVV under original manufacturing. All patients had successful engraftment but levels of gene therapy-derived hemoglobin (HbAT87Q) were lower than expected. Despite this, hemolysis markers and the annualized rate of vaso-occlusive crisis (VOCs) plus acute chest syndrome (ACS) were reduced post-infusion. Here, we provide an update on these patients and explore factors that may contribute to the clinical benefit. Data on patients treated more recently are presented separately. Methods Adults with SCD-related complications (previously described) were enrolled in HGB-206. All patients received myeloablative busulfan conditioning before DP infusion. The initial group (Group A; N=7) was treated with DP from BMH HSCs using the original LentiGlobin manufacturing process. The protocol was amended, and 2 patients were subsequently treated in Group B with DP from BMH HSCs. Patient 1 had DP made with original and refined manufacturing processes and patient 2 had DP made only with the refined process. Patients were followed for 2 years in HGB-206 and offered participation in the LTF-303 study for long-term follow-up. Adverse events (AEs), Hb fractions, and additional laboratory and clinical parameters were monitored. Results As of 7 March 2019, the median follow-up post-DP infusion was 35.8 (min-max: 29.8-44.5) months in Group A; it was 17.2 and 20.2 months for Group B patients 1 and 2. There was full hematological recovery with no graft failure. The safety profile of LentiGlobin post-DP infusion was consistent with myeloablative busulfan conditioning and underlying SCD. No cases of Grade ≥ 3 DP-related AEs, veno-occlusive liver disease, vector-mediated replication competent lentivirus or clonal dominance were observed. Three years after LentiGlobin gene therapy, one Group A patient developed myelodysplastic syndrome, reported as unlikely related to LentiGlobin. The patient subsequently received an HLA-haploidentical donor transplant. The annualized rate of VOCs plus ACS from LentiGlobin infusion to last follow-up was reduced by a median of 89 (min-max 10-100) % compared to that in the 2-year interval before enrollment in the 8 patients who had a history of VOC and/or ACS. One Group A patient who had a stroke pre-DP infusion has not had any red blood cell (RBC) transfusions through ~3 years post-DP infusion and no stroke recurrence. Median HbAT87Q levels were 1.0 (min-max 0.7-2.8) g/dL for Group A and 3.4 g/dL for Group B patient 1 at last visit and were stable for up to 3.5 years follow-up (Figure 1A). In several patients, HbF levels increased post-LentiGlobin treatment, peaking at ~2-6 months, and remaining higher at last visit compared to 1-month post-DP infusion. At last visit, the median HbF level was 0.6 (min-max 0.1-1.8) g/dL for all Group A and 0.8 g/dL for Group B patient 1 (Figures 1B and 2). In these patients, the median fraction of anti-sickling Hb (HbAT87Q + HbF + HbA2) was 22.9 (min-max 14.2-29.8) % and 39.4%, respectively. Patient 2 in Group B, who had DP made entirely using refined manufacturing process, had no HbF but produced high levels of HbAT87Q (7.5 g/dL) that contributed to 53.7% of total Hb. Summary In the HGB-206 Group A patients, the modest expression of gene therapy-derived HbAT87Q is accompanied by an induction of HbF. Elevated HbF levels have been shown to be associated with reduced severity of SCD. The resulting 14-30% of anti-sickling Hb observed in Group A patients, while not likely to be curative, showed clinical benefit as suggested by a reduction in the annualized rate of VOC plus ACS. Further, Group A and B patients have maintained HbAT87Q production, demonstrating the durability of gene therapy-derived β-globin gene expression. There have been no Grade ≥ 3 DP-related AEs in LentiGlobin-treated patients with up to 3.5 years of follow-up. Longer follow-up will help determine whether the initial induction of HbF, as is common after myeloablation, will be sustained and continue to contribute to therapeutic anti-sickling Hb levels. Disclosures Walters: Editas Medicine: Consultancy; TruCode: Consultancy; AllCells, Inc: Consultancy. Kwiatkowski:Apopharma: Research Funding; Imara: Consultancy; Celgene: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Terumo: Research Funding; Novartis: Research Funding. Schmidt:German Cancer Research Center, Heidelberg, Germany: Employment; GeneWerk GmbH, Heidelberg, Gemrany: Equity Ownership. Miller:bluebird bio, Inc.: Employment, Equity Ownership. Pierciey:bluebird bio, Inc.: Employment, Equity Ownership. Huang:bluebird bio, Inc.: Employment, Equity Ownership. Ribeil:bluebird bio, Inc: Employment, Equity Ownership. Kanter:Rockpointe: Honoraria; GLG: Consultancy; Guidepoint Global: Consultancy; Novartis: Consultancy, Honoraria; Imara: Consultancy; Sangamo: Consultancy, Honoraria; Modus: Consultancy, Honoraria; Medscape: Honoraria; Peerview: Honoraria; bluebird bio, Inc.: Consultancy; SCDAA: Membership on an entity's Board of Directors or advisory committees; NHLBI: Membership on an entity's Board of Directors or advisory committees; Jeffries: Consultancy; Cowen: Consultancy. Thompson:bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding.

Description: Abstract 3183 Poster Board III-120 Background Over the past 15 years, increased awareness and advances in management such as the widespread adoption of low molecular weight heparins and new anticoagulants have had a dramatic impact on practice; there are no large scale studies to determine the impact of these changes on the health care utilization and outcomes of DVT. We examined national statistics of the trends in hospital utilization for Deep Vein Thrombosis in the United States. Methods The Nationwide Inpatient Sample (NIS) is one in a family of databases and software tools developed as part of the Healthcare Cost and Utilization Project (HCUP), sponsored by the Agency for Healthcare Research and Quality. For 2007 NIS contains all discharge data from 1,044 hospitals located in 40 States, approximating a 20-percent stratified sample of U.S. community hospitals. We examined trends for hospital utilization available through the NIS dataset. All descriptive statistics have been reported for DVT as ‘primary discharge diagnosis’ as well as ‘All discharge diagnoses’. Presence of ICD-9-CM diagnosis codes 453.0-453.9 were used to define DVT related hospitalizations. Results From 1993 to 2007 the number of annual diagnosis of DVT as one of “All Diagnoses' of DVT annually increased from 224,739 to 526,105 while the number of DVT as ‘Principal Diagnosis’ increased from 110,445 to 146,612. The average length of hospital stay has decreased from 7.6 days to 5 days (p-value

Description: Abstract 2658 Introduction: Six minute walk distance (6MWD), is a measure of exercise capacity commonly used as an endpoint in pulmonary hypertension (PH) clinical trials. Many patients with sickle cell disease (SCD) have acute pain crises or chronic pain syndromes that impair their quality of life. While patients with SCD who are undergoing screening for PH are generally screened in steady state, i.e., when they have not had a recent pain crisis, the impact of chronic pain on exercise capacity in this group of patients has not been previously evaluated. Methods: walk-PHaSST was a multi-center screening study designed to identify subjects with SCD at increased risk for symptomatic PH, defined by a tricuspid regurgitant velocity (TRV) ≥ 2.7 m/sec and 6MWD between 150–500 meters, for enrollment in a double-blind placebo controlled trial of sildenafil. The primary endpoint was the change in 6MWD after 16 weeks of treatment. We examined the relationship between subjects' self-reported acute and chronic pain and baseline 6MWD in the screened SCD patients in walk-PHaSST. Results: For 90% of subjects, the information about pain was reported by the patient or parent/family member. Documentation of pain management and utilization of services was verified from medical records in 10% of subjects. Ninety four percent of all subjects reported having a history of acute sickle cell pain crises; 6% reported never having had an acute pain crisis. For the subjects who reported a history of acute pain crises, the ‘typical’ acute pain rating on a scale of 0 to 10 was ≥ 7 (maximum 10) for 77% of this subset of subjects. A total of 342 (50%) subjects reported not having had any pain crises in the preceding week. Of 720 subjects screened medical history and 6 MWD was available in 673 patients. Of these 633 (94%) subjects did not report having had a pain crisis requiring an emergency department visit or hospitalization in the preceding week. A total of 39% of subjects reported chronic sickle cell related pain; no rating was reported for chronic pain. 88% of patients reported using medications for pain control while 15% reported using non-drug therapy including physical therapy in 3%, alternative therapy in 2%, acupuncture in 2% and hypnosis in 〈 1% of patients. The mean 6MWD for the screened population was 439 meters (median 438 m, range 123–713 m). A total of 171/673 (26%) subjects had a 6MWD 〉500 meters, which was above the screening cut-off for enrollment in the main interventional trial. By univariate analysis, subjects reporting chronic pain had a significant lower odds ratio for walking 〉 500 meters (OR 0.637, 95% C.I 0.44–0.99); a similar observation was seen with those subjects with a history of acute pain crises (OR 0.47, 95% C.I 0.24–0.91). Multivariable logistic regression analysis revealed a significant inverse relationship between chronic pain but not acute pain and 6MWD after adjusting for age, TRV, gender, hematocrit and smoking history (See Table 1). The mean 6MWD decreased by 27 meters with self reported chronic pain after adjusting for TRV, age, gender, hematocrit and 6MWD. Conclusions: TRV is a known predictor of 6MWD. However, these data suggest that patient self reported sickle cell related chronic pain is also an independent predictor of 6MWD. This relationship raises interesting questions about the potentially confounding effects of pain on exercise capacity as assessed by the 6MW test. Further study is warranted to investigate an association between chronic pain and exercise capacity in SCD as well as exploration of appropriate endpoints for future clinical trials in patients with SCD and suspected symptomatic PH. Disclosures: Barst: Pfizer: Consultancy, Research Funding. Rosenzweig:Pfizer: Research Funding. Badesch:Pfizer: Honoraria, Research Funding. Hassell:Novartis: Research Funding.

Description: Background: Hematopoietic cell transplantation (HCT) for sickle cell disease (SCD) is potentially curative, yet applied sparingly in adults due in part to limited donor availability and to concerns about safety. We conducted a multicenter pilot clinical trial to determine ways to broaden the availability of this therapy. Objective: To determine the feasibility, efficacy, and safety of a reduced toxicity transplant conditioning regimen in adults with severe SCD receiving related and unrelated donor HCT. Methods: Patients between 16-40 years of age were enrolled between October 2012 and June 2015 at 8 participating transplant centers. Eligibility criteria included stroke; recurrent episodes of acute chest syndrome (ACS) or sickle pain in the past 2 years; 8 or more RBC transfusions/year; or a tricuspid valve regurgitant jet velocity ³2.7 m/sec. Patients received unmodified bone marrow from a human leukocyte antigen (HLA)-matched sibling or an unrelated donor matched for 8 of 8 HLA loci. Patients were prepared for HCT with Busulfan from day -8 to -5 (13.2 mg/kg), Fludarabine from day -7 to -3 (150 mg/m2) and Thymoglobulin from day -5 to -2 (6 mg/kg). GVHD prophylaxis consisted of cyclosporine or tacrolimus with methotrexate. Outcomes and Measures: The primary endpoint was event-free survival 1 year after HCT, with events defined as graft failure, disease recurrence, or death. The Kaplan-Meier probabilities of event-free and overall survival were determined. Donor chimerism, transplant-related toxicities and clinical and laboratory measures of SCD were secondary endpoints obtained 1 year after HCT. Serious adverse events were monitored after transplantation. Results: Twenty-two patients (13 were female) who ranged in age from 17-36 (median 22) years were enrolled. Seventeen patients received a sibling and 5 an unrelated donor HCT. An eligibility review committee confirmed subject eligibility. Enrolled subjects had stroke (2 pts), ACS (3 pts), painful crises (14 pts), RBC transfusions (6 pts) and/or tricuspid valve regurgitant jet velocity (5 pts); 8 subjects satisfied eligibility criteria for more than 1 category. There were 6 severe adverse events after transplantation in 4 patients including one death from intra-cranial hemorrhage related to posterior reversible encephalopathy syndrome. None of the patients had graft failure or SCD recurrence after HCT. Currently, 21 of 22 patients survive with stable engraftment of donor cells at a median 9.7 months (range, 1-31) after HCT. The overall and event-free survival probabilities are both 95% (90% CI 76%; 99%, Figure 1) at 12-months after HCT. Two patients developed grade I skin acute GVHD and three patients developed chronic GVHD. Full donor myeloid chimerism was observed after HCT. The median donor T-cell and RBC chimerism at 28, 100 and 180 days after HCT was 55.5% and 100%, 80% and 100%, and 87.5% and 100%, respectively. Conclusions: We report excellent outcomes after HLA-matched HCT in adults with SCD using a reduced toxicity-conditioning regimen performed in a multi-center setting. We observed very low rates of graft rejection and GVHD in this pilot study. We speculate that these outcomes, if sustained long-term after HCT, will be superior to survival in adults with SCD who receive standard supportive care. If confirmed in a larger comparative trial, this approach would broaden the availability and application of transplantation for adults with severe SCD. Figure 1. Figure 1. Disclosures Walters: ViaCord and AllCells, Inc: Other: Medical director.