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Thalassaemia is caused by genetic globin defects leading to anaemia, transfusion-dependence and comorbidities. Reduced survival and systemic organ disease affect transfusion-dependent thalassaemia major and thalassaemia intermedia. Recent improvements in clinical management have reduced thalassaemia mortality. The therapeutic landscape of thalassaemia may soon include gene therapies as functional cures. An analysis of the adult US thalassaemia population has not been performed since the Thalassemia Clinical Research Network cohort study from 2000 to 2006. The Centers for Disease Control and Prevention supported US thalassaemia treatment centres (TTCs) to compile longitudinal information on individuals with thalassaemia. This dataset provided an opportunity to evaluate iron balance, chelation, comorbidities and demographics of adults with thalassaemia receiving care at TTCs. Two adult cohorts were compared: those over 40 years old (n = 75) and younger adults ages 18-39 (n = 201). The older adult cohort was characterized by higher numbers of iron-related comorbidities and transfusion-related complications. By contrast, younger adults had excess hepatic and cardiac iron and were receiving combination chelation therapy. The ethnic composition of the younger cohort was predominantly of Asian origin, reflecting the demographics of immigration. These findings demonstrate that comprehensive care and periodic surveys are needed to ensure optimal health and access to emerging therapies.

We introduce a paradigm of completely non-invasive, on-demand diagnostics that may replace common blood-based laboratory tests using only a smartphone app and photos. We initially targeted anemia, a blood condition characterized by low blood hemoglobin levels that afflicts >2 billion people. Our app estimates hemoglobin levels by analyzing color and metadata of fingernail bed smartphone photos and detects anemia (hemoglobin levels, Anemia has a global prevalence of over 2 billion people and is diagnosed via blood-based laboratory test. Here the authors describe a smartphone app that can estimate hemoglobin levels and detect anemia by analyzing pictures of fingernail beds taken with a smartphone and without the need of any external equipment.

BACKGROUND. Anemia, or low blood hemoglobin (Hgb) levels, afflicts 2 billion people worldwide. Currently, Hgb levels are typically measured from blood samples using hematology analyzers, which are housed in hospitals, clinics, or commercial laboratories and require skilled technicians to operate. A reliable, inexpensive point-of-care (POC) Hgb test would enable cost-effective anemia screening and chronically anemic patients to self-monitor their disease. We present a rapid, standalone, and disposable POC anemia test that, via a single drop of blood, outputs color-based visual results that correlate with Hgb levels. METHODS. We tested blood from 238 pediatric and adult patients with anemia of varying degrees and etiologies and compared hematology analyzer Hgb levels with POC Hgb levels, which were estimated via visual interpretation using a color scale and an optional smartphone app for automated analysis. RESULTS. POC Hgb levels correlated with hematology analyzer Hgb levels (r = 0.864 and r = 0.856 for visual interpretation and smartphone app, respectively), and both POC test methods yielded comparable sensitivity and specificity for detecting any anemia (n = 178) (

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

Patients with thalassemia have low circulating levels of many nutrients, but the contribution of dietary intake has not been assessed.Our objective was to assess dietary intake in a large contemporary sample of subjects with thalassemia.A prospective, longitudinal cohort study using a validated food frequency questionnaire was conducted.Two hundred and twenty-one subjects (19.7±11.3 years, 106 were female) were categorized into the following age groups: young children (3 to 7.9 years), older children/adolescents (8 to 18.9 years), and adults (19 years or older); 78.8% had β-thalassemia and 90% were chronically transfused. This study took place at 10 hematology outpatient clinics in the United States and Canada.We conducted a comparison of intake with US Dietary Reference Intakes and correlated dietary intake of vitamin D with serum 25-OH vitamin D and dietary iron with total body iron stores.Intake was defined as inadequate if it was less than the estimated average requirement. χ(2), Fisher's exact, and Student's t test were used to compare intake between age categories and logistic regression analysis to test the relationship between intake and outcomes, controlling for age, sex, and race.More than 30% of subjects consumed inadequate levels of vitamin A, D, E, K, folate, calcium, and magnesium. The only nutrients for which90% of subjects consumed adequate amounts were riboflavin, vitamin B-12, and selenium. Dietary inadequacy increased with increasing age group (P0.01) for vitamins A, C, E, B-6, folate, thiamin, calcium, magnesium, and zinc. More than half of the sample took additional supplements of calcium and vitamin D, although circulating levels of 25-OH vitamin D remained insufficient in 61% of subjects. Dietary iron intake was not related to total body iron stores.Subjects with thalassemia have reduced intake of many key nutrients. These preliminary findings of dietary inadequacy are concerning and support the need for nutritional monitoring to determine which subjects are at greatest risk for nutritional deficiency. Future research should focus on the effect of dietary quality and nutritional status on health outcomes in thalassemia.

An elevated tricuspid regurgitant jet velocity (TRV) is associated with hemolysis and early mortality in sickle cell disease, yet risk factors, clinical parameters, and mortality associated with this biomarker in thalassemia are poorly defined. This report summarizes the prevalence of an elevated TRV in 325 patients screened by Doppler echocardiography in the Thalassemia Clinical Research Network. A documented TRV was reported in 148 of 325 (46%) of patients. Average age was 25.9 years (range, 5-56 years) and 97% were transfusion-dependent. Mean TRV was 2.3 ± 0.4 m/s (range, 0.2-3.5 m/s). An abnormal TRV ≥ 2.5 m/s was identified in 49 of 148 (33%) of patients with a documented TRV, 5% (8/148), with a TRV ≥ 3.0 m/s, suggesting significant PH risk. Older age was strongly associated with a high TRV; however, 16% of children had a TRV ≥ 2.5 m/s. A history of splenectomy, hepatitis C, smoking, or high white blood cell count was associated with TRV elevation. In summary, an elevated TRV is noted in one-third of transfusion-dependent thalassemia patients with a documented value and develops in both children and adults. Age, splenectomy, hepatitis C, and smoking are significant univariate risk factors, with splenectomy surfacing as the dominant risk factor over time. Mortality was low in this cohort. Prospective longitudinal studies are needed. This study is registered at http://www.clinicaltrials.gov as NCT00661804.

Morbidity and mortality in thalassemia are associated with iron burden. Recent advances in organ-specific iron imaging and the availability of oral deferasirox are expected to improve clinical care, but the extent of use of these resources and current chelation practices have not been well described. In the present study, we studied chelation use and the change in iron measurements in 327 subjects with transfusion-dependent thalassemia (mean entry age, 22.1 ± 2.5 years) from 2002-2011, with a mean follow-up of 8.0 years (range, 4.4-9.0 years). The predominant chelator currently used is deferasirox, followed by deferoxamine and then combination therapies. The use of both hepatic and cardiac magnetic resonance imaging increased more than 5-fold (P < .001) during the study period, leading to an 80% increase in the number of subjects undergoing liver iron concentration (LIC) measurements. Overall, LIC significantly improved (median, 10.7 to 5.1 mg/g dry weight, P < .001) with a nonsignificant improvement in cardiac T2* (median, 23.55 to 34.50 ms, P = .23). The percentage of patients with markers of inadequate chelation (ferritin > 2500 ng/mL, LIC > 15 mg/g dry weight, and/or cardiac T2* < 10 ms) also declined from 33% to 26%. In summary, increasing use of magnetic resonance imaging and oral chelation in thalassemia management has likely contributed to improved iron burden.

Thalassemia is one of the most common monogenic diseases of man, prevalent in tropical and subtropical regions of the world. Population migration during the past decades has led to increasing numbers of these patients being encountered in all parts of the world, including in the United States. A

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 2016 Poster Board I-1038 BACKGROUND: Pulmonary hypertension (PH) contributes to heart disease, the leading cause of death in thalassemia. PH in thalassemia is multifactorial, including oxidative stress, hemolysis, thrombosis, splenectomy, abnormal arginine-nitric oxide bioavailability, and iron overload. Despite the high mortality rate associated with PH, no intervention studies in thalassemia have been completed. This report summarizes the prevalence of elevated tricuspid regurgitant jet velocity (TRV) as a proxy for PH in patients clinically screened by Doppler echocardiography (echo) in the Thalassemia Clinical Research Network (TCRN). PATIENTS AND METHODS: The TCRN is an NIH-sponsored network of major thalassemia centers in the US, Canada and London, UK. This analysis is part of the Thalassemia Longitudinal Cohort (TLC), which collects longitudinal data from 428 patients at 16 centers. We report results from 303 patients (71%) who were assessed by echo at least once. Predictors considered for analysis were age, gender, splenectomy, hepatitis C, WBC, ferritin, hemoglobin, liver function, creatinine, chronic transfusion status, number of transfusions, chelation status, and hydroxyurea use. Multivariate effects of predictors significant in univariate analysis were modeled using logistic regression for elevated TRV. RESULTS: Measurable TRV jet was detectable in 144/303 (48%) of patients. Average age of the cohort with a detectable TRV was 25.8 years (range 5-56 years); half were female.. 97% of the patients studied were transfusion dependent. Mean TRV was 2.3±0.4 m/s (range 0.2-3.5 m/s). An abnormal TRV ≥ 2.5 m/s was identified in 45/144 (31%) of patients screened, 18% (8/45) of whom had a TRV ≥ 3.0 m/s suggesting significant PH. Older age was strongly associated with PH (r = 0.38, p CONCLUSIONS: Elevated TRV is noted in at least 1/3 of transfusion-dependent thalassemia patients with measurable TR jets. We observed elevated TRV in both children and adults. Less than half of patients screened by echo had a measurable TRV, suggesting that technical diligence is needed to increase the fraction of echos with a measured TRV to better identify patients at risk of PH. Age, splenectomy and history of hepatitis C are significant univariate risk factors in this population, with age remaining an independent risk factor in multiple regression analysis. Ongoing assessment in the TLC and specific prospective longitudinal studies of PH in thalassemia are needed to understand the natural history and pathophysiology in thalassemia in order to determine optimal therapy. Interventional trials for PH in thalassemia are needed. Disclosures: No relevant conflicts of interest to declare.

Abstract 1371 Poster Board I-393 The study examines the quality of life (QOL) of pediatric thalassemia patients and their families enrolled in the Thalassemia Longitudinal Cohort (TLC) study of the NHLBI-sponsored Thalassemia Clinical Research Network, which comprises 17 centers in the US, Canada, and London, UK. The study evaluates 99 baseline responses to the Children's Health Questionnaire (CHQ) PF28, a self-administered survey filled out by the parent or guardian of patients age 5 y and older. The CHQ utilizes 12 scales that can be grouped into parental assessments of the child's physical well-being; mental, emotional and behavioral health; and the familial context. We previously showed that compared to the US population, the thalassemia population is significantly different on 7 of the 12 scales. Here we evaluate these data by patient gender, race, age, and chelator type. The mean age of the population was 9.7 y (range 5.0-13.8 y), with 48% male, and 65% non-white. While parents assessed males to have a lower QOL than females, the only significant difference was in their assessment of the child's emotional role/behavior (school or friends). When comparing white to non-white (predominantly Asian) patients, with the exception of bodily pain, non-white thalassemia patients reported poorer PF28 scores. However, only the reported impact on parental time and emotion are significant. These variances appear to mirror the US population. Figure 1 shows PF28 summary scores by age in thalassemia compared to the general US population. Parents evaluate their child with thalassemia with lower physical health than US norms (p Finally, when CHQ PF28 assessments are compared by chelator type (subcutaneous deferoxamine vs. oral deferasirox), parents report that children receiving deferoxamine have generally lower QOL than the rating for those receiving Deferasirox. However, the only significant differences are with perceived physical function, impact on family activities, and the overall physical summary scale. The CHQ PF28 data provides important insight into the impact the child with thalassemia has on the family. Although psychosocial QOL is similar, children, and especially adolescents, with thalassemia have lower physical QOL, especially those on chelation with Deferoxamine. Because PF28 takes the parents' point of view, it can't be determined from these data alone whether the reported difference between parenteral and oral chelator would hold true for direct patient assessments. The gender of the child also appears to affect parental expectation of the child's QOL. These data validate the observational evidence that a child with thalassemia has a significant impact on the family. Figure 1 TLC CHQ PF28 Summary Scales compared to US norms Figure 1. TLC CHQ PF28 Summary Scales compared to US norms Disclosures: Odame: Novartis: Consultancy, Speakers Bureau. Thompson: Novartis: Research Funding. Neufeld: Novartis: Research Funding.

Abstract 4056 Poster Board III-991 BACKGROUND Survival in thalassemia is strongly influenced by iron burden and adherence to chelation therapy. Deferoxamine (DFO) is an effective chelator, in use since the 1970s, but the parenteral mode of administration hinders adherence. Deferasirox (DFX), taken orally, became commercially available in the US in Jan. 2006, and deferiprone (DFP) is only available in North America (N.A.) through research or compassionate use. The impact of expanded chelation options on iron burden in thalassemia patients has not been studied. The goals of this study were to assess the chelator choices among patients with thalassemia and to compare efficacy and treatment adherence among chelators. METHODS The TCRN is a NHLBI-sponsored clinical trial network of Thalassemia Centers in N. A. and London, U.K. The Thalassemia Longitudinal Cohort (TLC) study of the TCRN was launched in 2006. Baseline data collection included a five-year retrospective component, with clinical, radiographic, and laboratory data from 2002 onward. This is followed by annual prospective data collection thereafter. The current analyses include data from the retrospective portion through baseline assessment. The dates of data collection span the initiation of DFX, first in clinical trials and then in routine clinical use. RESULTS Of the 404 enrolled subjects, 317 had ever received chelation therapy. Mean age was 21.2 ± 12.1y, and 46.4% were male. Genotype distribution included beta-thal major (79.2%), beta-thal intermedia (6.6%), chronically transfused HbE-beta-thal (9.5%), Hb E-beta-thal, not chronically transfused (1.6%), chronically transfused alpha-thal syndromes (2.3%), and other (1%). The median ferritin level was 1431 ng/mL (range, 122-23712 ng/mL) and mean liver iron content (LIC) was 10.8 mg/g dw (0.3-43.3 mg/g dw). Current choices are: DFO (27%), DFX (58%), DFP (1%), combination DFO+DFP (5%), DFO+DFX (3%), and no chelation (7%). Among chelated patients, 65 (21%, mean age 19.1y) chose to continue DFO and never used DFX, while 192 (61%, mean age 21.9y) have taken DFX (p=0.1). The mean current doses of DFO and DFX were 39 mg/kg/day and 25 mg/kg/day, respectively. Compared to those who switched to DFX, patients who continued DFO had lower initial ferritin levels (1499 DFO v. 2144 ng/mL DFX, p=0.02), but similar LICs (14.1 v 13.9 mg/g dw, p=0.9). Reasons for switching to DFX included: participation in clinical trials before 2006 (26%), commercial availability of drug (27%), patient/family preference (22%), high iron burden (15%), and other (10%). Conversely, 32 subjects who tried DFX switched back to DFO for the following reasons: patient/family preference (38%), high iron burden on DFX (16%), renal dysfunction (6%), elevated alanine aminotransferase (3%), and other (37%). Over the 5-year period, patients currently receiving DFX had a significant reduction in LIC (13.3 to 10.9 mg/g dw, p=0.02) and a trend towards reduction in ferritin level (2198 to 2027 ng/mL, p=0.06), while those receiving DFO had no significant change in LIC (12.2 to 10.4 mg/g dw. P=0.17) but had a significant decrease in ferritin levels (1881 to 1516 ng/mL, p=0.04). Self-reported treatment adherence was higher in the DFX group than in the DFO group, with 89% compared with 76.5% reporting adherence at least 75% of the time (p=0.02). Twenty-seven percent of patients on DFO at study entry and 30% of patients on DFX have ferritin >2500 ng/mL and/or LIC >15 mg/g d.w., indices of inadequate chelation. CONCLUSIONS DFX is currently the predominant chelator choice among patients with thalassemia in the TCRN. LIC appeared to improve among patients who have switched to DFX between 2002 and baseline TLC studies in 2007-2009, although ferritin remained stable. In the same time period, for DFO treated patients, ferritin significantly decreased but the LIC did not change. Nevertheless, the final LIC was similar between DFO and DFX treated groups. Inadequate control of iron burden was observed in a significant subset of patients receiving either chelator; thus, close monitoring of iron burden and encouragement and support of adherence are essential. Disclosures: Thompson: Novartis: Consultancy, Honoraria. Mueller:Novartis: Site principal investigator. Odame:Novartis: Consultancy, Speakers Bureau. Giardina:Novartis: Research Funding. Vichinsky:Novartis: Consultancy, Research Funding. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Coates:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Neufeld:Novartis: Research Funding.

Ten patients had repeated measurements of the their midventricular T2* imaging, and an additional 8 patients had measurements at three slice locations (9/18 males, median age 19.3 years, range 11.2-23.6 years). For the initial 10 patients, the median T2* value was 21.3 ms (range 6.336.0), with a median standard deviation of 1.5 ms (range 0.1-4.4) at the mid-ventricular level. Two of ten patients had values that spanned the clinically accepted cut-point of 20 ms, indicating they could have been classified as either normal or mildly abnormal depending on which image was selected for analysis. For the 8 patients with multiple slice locations analyzed, the median T2* values were 29.5 ms (9.5-47.2), 25.9 (12.5-37.3), and 22.7 (9.933.7) for the apex, mid, and basilar levels respectively. While the median standard deviations for each slice location were low (0.6, 0.9, and 0.5 respectively), the differences between the slice locations resulted in 1 patient having values both above and below 20 ms, and 2 additional patients with values above and below the “severely abnormal” cut-point of 10 ms. Conclusions