ALBERT

Description: Recent molecular studies of fetal hemoglobin (HbF) regulation have reinvigorated the field and shown promise for the development of clinical HbF inducers to be used in patients with β-thalassemia and sickle cell disease. However, while numerous promising inducers of HbF have been studied in the past in β-thalassemia patient populations, with limited success in some cases, no universally effective agents have been found. Here we examine the clinical studies of such inducers in an attempt to systematically review the field. We examine trials of agents, including 5-azacytidine, hydroxyurea, and short-chain fatty acids. This review highlights the heterogeneity of clinical studies done on these agents, including both the patient populations examined and the study end points. By examining the published studies of these agents, we hope to provide a resource that will be valuable for the design of future studies of HbF inducers in β-thalassemia patient populations.

Description: Abstract 5167 Introduction: Despite favorable effect on survival, the burden of chronic transfusion and iron chelation therapy in patients with thalassemia major (TM), alongside clinical complications of the disease, still pose a negative impact on patients' quality of life (QOL) and mental health. In patients with thalassemia intermedia (TI), the milder nature of the disease and transfusion-independence in many cases, imply better psychosocial adaptation. However, the unbalanced, chronic underlying pathophysiology of the disease still allows for several serious clinical complications to manifest, which may have a negative impact on patients' QOL and mental health. We herein evaluate the prevalence of anxiety and depression in TI as compared to TM patients. Method: This was a cross-sectional, questionnaire-based study on TI (transfusion- and iron chelation-independent) and TM (regularly transfused and iron chelated) patients attending the Chronic Care Center, Hazmieh, Lebanon. Institutional review board approval was obtained and all participating patients signed an informed consent. A total of 81 patients agreed to participate in the study (33 TI and 48 TM). The State Trait Anxiety Inventory (STAI) questionnaire was used to assess anxiety level of patients. The questionnaire was previously translated, adapted and validated on the Lebanese population. The Beck Depression Inventory (BDI) questionnaire was used to assess depression level of patients. It was also previously translated and administered to a Lebanese population. Data on patient demographics, socioeconomic status, and disease complications (cardiovascular, gastrointestinal, and endocrine) were collected. Result: Patients with TI and TM were comparable in demographics, socioeconomic status, and number of disease complications (Table 1). TI patients had a significantly higher State Anxiety score than TM patients (40.9 ± 12.2 vs. 34.9 ± 21.1; P=0.031) and a higher yet not statistically significant Trait Anxiety score (42.1 ± 11.1 vs. 38.0 ± 11.5; P=0.117). Mean scores of both patient groups fell within norms reported for a healthy Lebanese sample. A higher, yet not statistically significant, proportion of TI patients suffered some form of depression compared to TM (TI, 45.5% [21.2% mild, 9.1% mild-moderate, 12.1% moderate-severe, 3.0% severe] vs. TM, 29.2% [18.8% mild, 4.2% mild-moderate, 6.2% moderate-severe, 0.0% severe]; P=0.133). Conclusion: Advances in medical therapy allowed TM patients to lead almost normal lives. However, the burden of disease treatment and complications still present significant challenge and may affect mental health, notably, a high rate of depression. Transfusion-independent patients with TI show a similar rate of depressive symptoms that could be partially attributed to the high number of complications associated with the disease. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1030 Background: As the ideal assessment and management strategies of iron overload in patients with β-thalassemia major (TM) remain unclear, evaluation of real-life experiences is warranted. Methods: This was a cross-sectional study of 924 TM patients actively treated at nine Italian centers. Data were retrieved on 15-09-2009 through a common software (Webthal®) used by participating centers, and included: demographics; splenectomy and transfusion history; detailed iron overload assessment history; type of iron chelator used; existence of hepatitis C virus, heart disease, or diabetes mellitus; alanine aminotransferase and serum creatinine levels. Results: The mean age of patients was 30.1 ± 9.1 years (48.8% males, 42.8% splenectomized). Among the 924 patients, 83.9% had at least one previous liver iron concentration (LIC) measurement and 68.7% had it within two years prior. On step-wise multivariate logistic regression, a serum ferritin level 2 years. Moreover, 69.6% had at least one previous CMR T2* measurement and 73.4% patients had it within two years prior. Patients who never had a CMR T2* were 2500 ng/ml or CMR T2*

Description: To evaluate the association between fetal hemoglobin (HbF) levels and morbidity in β-thalassemia intermedia (TI), we analyzed data from 63 untransfused patients who had also never received HbF induction therapy. Patient records were reviewed for any history of 10 predefined morbidities. Laboratory measurements for markers of ineffective erythropoiesis were also obtained. The mean age of patients was 32.1 years, 47.6% were males, and the median HbF level was 37.2%. HbF levels correlated positively with total hemoglobin, yet negatively with growth differentiation factor-15 and non–transferrin-bound iron levels. Median HbF levels were significantly lower in patients with the majority of evaluated morbidities than in those without. There was a strong negative adjusted linear correlation between the HbF level and the total number of morbidities (R2 = 0.825, P 〈 .001). The HbF threshold of 63.7% had 95.5% sensitivity and 100% specificity for ensuring absence of morbidity. There exists a strong association between HbF levels and morbidity in the subset of untransfused patients with TI.

Description: Introduction: Previous studies have examined the total healthcare resource utilization (HCRU) of patients with beta-thalassemia in relation to the general population. However, limited studies have examined the impact of red blood cell transfusion (RBCT) burden on broad aspects of HCRU beyond transfusion costs among patients with beta-thalassemia. Methods: Patients with beta-thalassemia in Taiwan's National Health Insurance Research Database (NHIRD) in 2016 were identified (International Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] of D56.1). The index date was the first medical claim in the database after 2001. Identified patients were followed from the index date until the end of the study period (December 31, 2016). During the follow-up period, RBCT units and HCRU (all-cause and thalassemia-related) were measured. Thalassemia-related HCRU was defined as any HCRU claim accompanied by a thalassemia or beta-thalassemia diagnosis code. To control for the different lengths of follow-up between patients, both RBCT units and HCRU were reported as the average per 12 weeks over the entire follow-up period. Patients were categorized into 4 cohorts based on the average number of RBCT units received per 12 weeks during follow-up: 0 RBCT units; 〉 0 to 〈 6 RBCT units; ≥ 6 to 〈 12 RBCT units; or ≥ 12 RBCT units. HCRU outcomes of interest were hospital admissions, hospitalized days, outpatient visits, and emergency room (ER) visits. Descriptive statistics were computed to describe HCRU observed in each cohort. Results: A total of 2,984 patients with beta-thalassemia were included in the analysis, with a mean follow-up of 6.87 years. Mean age at index was 37.8 (standard deviation 23.7) years, and 1,903 (63.8%) patients were female. A total of 1,616 (54.2%) patients did not receive RBCT units during the follow-up period. Of the remaining 1,368 patients, 1,112 (81.3%) received 〉 0 to 〈 6 RBCT units, 112 (8.2%) received ≥ 6 to 〈 12 RBCT units, and 144 (10.5%) received ≥ 12 RBCT units per 12 weeks during follow-up. Mean all-cause and thalassemia-related HCRU was higher for transfused patients than for non-transfused patients across all HCRU categories. Thalassemia-related hospital admissions, hospitalized days, and outpatient days all increased as the transfusion burden increased. Patients in the cohort with the highest average transfusion burden (≥ 12 RBCT units per 12 weeks) had numerically greater mean thalassemia-related hospital admissions (0.5; standard error [SE] = 0.04), hospitalized days (2.5; SE = 0.21), and outpatient visits (4.9; SE = 0.41) than the other cohorts (Figure). Conclusions: Patients with beta-thalassemia and higher average transfusion burden during the follow-up period had additional HCRU compared with patients who required fewer RBCT units. These data may support physician and payer understanding of the downstream economic impact of RBCT burden in beta-thalassemia. Disclosures Tang: GSK: Consultancy; Roche: Research Funding; Pfizer: Research Funding; Janssen: Research Funding; Amgen: Research Funding. Furnback:Sanofi: Consultancy; Regeneron: Consultancy; Celgene Corporation: Consultancy; Abbott: Consultancy; Astellas: Consultancy; Pfizer: Consultancy; Eli Lilly: Consultancy; Janssen: Consultancy; Johnson & Johnson: Consultancy; Gilead: Consultancy; Novocure: Consultancy; Progentec Diagnostics: Consultancy; Becton Dickinson: Consultancy; AstraZeneca: Consultancy; Bristol-Myers Squibb: Consultancy. Wang:Gilead Sciences: Consultancy, Equity Ownership; Celgene Corporation: Consultancy, Equity Ownership; Regeneron Pharmaceuticals: Consultancy, Equity Ownership; Novocure: Consultancy; Pfizer: Consultancy; Eli Lilly: Consultancy; Johnson & Johnson: Consultancy; Astellas: Consultancy; Amgen, Vertex Pharma, Illumina, Biogen, Alexion Pharma, Incyte, Biomarin Pharma, Seattle Genetics, Sarepta Therapeutics, Array Biopharma, Ionis Pharma, Sage Therapeutics, Mylan NV, Neurocrine Biosciences, Bio Techne Corp, Jazz Pharma, Alnylam Pharma, Blue: Equity Ownership. Tang:Asclepius Analytics: Employment. Huang:Celgene Corporation: Employment. Tang:Celgene Corporation: Employment, Equity Ownership. Musallam:Celgene Corporation: Consultancy.

Description: Abstract 1024 Background: We previously established an association between increasing liver iron concentration (LIC) and vascular as well as endocrine/bone disease in patients with β-thalassemia intermedia (TI) (Musallam et al. Haematologica 2011). More recently, a randomized clinical trial showed the efficacy and safety of deferasirox for the treatment of iron overload in TI patients with a LIC ≥5 mg Fe/g dry weight (dw) (Taher et al. Blood 2012). The aim of this analysis was to evaluate the association of the 5 mg Fe/g dw threshold with vascular and endocrine/bone morbidity in TI patients. Methods: We analyzed data from a cross-sectional study of 168 TI patients who never received iron chelation therapy. For each patient, iron burden was determined directly by measuring LIC using magnetic resonance imaging. Data on the occurrence of vascular (thrombosis or pulmonary hypertension) as well as endocrine/bone (hypothyroidism, osteoporosis, or hypogonadism) morbidities were also retrieved. Splenectomy status and transfusion history, as well as total hemoglobin level at the time of LIC measurement were also determined. Results: The mean age of patients was 35.2 ± 12.6 years (range: 8–66 years) with 42.9% being males and 72.0% being splenectomized. The mean total hemoglobin level was 8.8 ± 1.6 g/dl, with 26.2% being completely transfusion-naive while the remaining patients had received some form of transfusion therapy for specific complications and for defined periods of time. The mean LIC was 8.4 ± 6.7 mg Fe/g dw (range: 0.5–32.1 mg Fe/g dw), with 70 (41.7%) patients having a LIC of

Description: In the STOP II trial, discontinuation of prophylactic transfusions in high risk children with sickle cell disease (SCD) resulted in a high rate of reversion to abnormal blood-flow velocities on transcranial Doppler (TCD) ultrasonography and strokes. We analyzed data from STOP II to determine the effect of discontinuing transfusions on the development or progression of silent brain infarcts on magnetic resonance imaging (MRI). At study entry, 21 of 79 (27%) patients had evidence of silent infarcts. There were no statistically significant differences in baseline characteristics between patients with normal brain MRI or silent infarcts at study entry. At study end, 3 of 37 (8.1%) patients in the continued-transfusion group developed new brain MRI lesions compared with 11 of 40 (27.5%) in the transfusion-halted group (P = .03). The total number of lesions remained essentially unchanged decreasing from 25 to 24 in the continued-transfusion group while increasing from 27 to 45 in transfusion-halted patients. Thus, discontinuation of transfusions in children with SCD and abnormal TCD who revert to low-risk increases the risk of silent brain infarction. Together with data from STOP, these findings demonstrate that transfusions prevent the development of silent infarcts in patients with SCD and abnormal TCD but normal MRA.

Description: Abstract 1021 Background: An association between iron overload and morbidity in patients with β-thalassemia intermedia (TI) has been established. However, available studies relied on cross-sectional analysis (measures of prevalence rather than incidence) without a clear chronological relationship between risk factors and outcomes. Methods: We conducted a retrospective cohort study of TI patients treated at five comprehensive care centers in Italy, Lebanon, Oman, Iran and Egypt. We included all patients attending the centers since 01 January 2000 and regularly followed until 31 December 2009 or death. For each patient, we retrieved serum ferritin (SF) and total hemoglobin (Hb) levels for every year during the 10-year follow up period, and calculated the average SF and total Hb levels during the study period (10-year indices). Moreover, we retrieved data on the incidence of nine pre-defined morbidities during the study period. Data on splenectomy status was also retrieved. For this preliminary study, we analyzed data from the first 52 recruited patients. None of the patients were regularly transfused or iron chelated during the study period. Results: The mean age of patients at study entry was 24.1 ± 11.3 years with 48.1% of patients being males. Thirty (57.7%) patients were splenectomized. The mean SF-index was 714.3 ± 518.7 ng/ml (range: 38.4 to 1926.2 ng/ml) and the mean Hb-index was 8.9 ± 1.2 g/dl (range: 7–12 g/dl). None of the patients died during the study period. Thirty-six patients experienced a morbidity during the study period, giving a 10-year cumulative incidence of 69.2% (19 [36.5%] had a single morbidity while 17 [32.7%] had multiple morbidities). The most common morbidity was osteoporosis (48.1%) followed by extramedullary hematopoiesis (19.2%), liver disease (17.3%), hypothyroidism (9.6%), diabetes mellitus (7.7%), hypogonadism (7.7%), thrombosis (5.8%), pulmonary hypertension (1.9%), and hypoparathyroidism (1.9%). The mean SF-index was higher in patients who developed morbidity than those who did not (877.5 vs. 346.9 ng/ml, p1000 ng/ml threshold was non-estimable (all patients with a SF-index of 〉1000 ng/ml developed a morbidity). Conclusion: There exists a clear association between elevations in SF level and an increased risk of morbidity in TI patients, further supporting the need for iron chelation therapy in this patient population. The relative risk becomes considerably high for increases beyond 300 ng/ml. Disclosures: Musallam: Novartis Pharmaceuticals: Honoraria. Cappellini:Novartis Pharmaceuticals: Speakers Bureau. Taher:Novartis: Honoraria, Research Funding.

Description: Abstract 904 Background: As a result of previous transfusions, β-thalassemia major (TM) patients who have undergone curative hematopoietic stem cell transplantation (HSCT) are at increased risk of iron overload. There are, however, limited data on iron removal in such patients with either phlebotomy (PHL) or iron chelation. The aim of this study was to compare the efficacy, safety and convenience of the oral iron chelator deferasirox (DFX; Exjade®) with PHL for the treatment of iron overload in children with TM following HSCT, over a 1-year period. Methods: LB03T is a prospective, randomized trial enrolling children with TM aged 2-3 mg Fe/g dry weight [dw]). Eligible patients were randomized to PHL (6 mL/kg blood/2 weeks) or DFX (10 mg/kg/day starting dose; 5 mg adjustments up to 20 mg/kg/day were permitted). One of the primary endpoints was change in LIC assessed using magnetic resonance imaging techniques. Changes in serum ferritin levels, hemoglobin (Hb), total iron binding capacity (TIBC), non-transferrin-bound iron (NTBI), adverse events (AEs) and compliance with study treatment (PHL: ratio of performed:planned; DFX: tablet count) were also assessed. Convenience of treatment was evaluated using parents' responses to pre-prepared questions. Results: 27 patients were randomized to DFX or PHL; one patient randomized to PHL refused treatment, hence 12 patients received DFX and 14 received PHL. Mean age was 12.4 yrs and 53.8% were male. Patients were followed up for a mean of 12.0 months. 2 and 5 patients had DFX dose increases to 15 and 20 mg/kg/day, respectively. Mean DFX dose at last visit was 11.0 and 18.1 ng/mL in the LIC≤7 and LIC〉7 groups, respectively. Median serum ferritin was significantly reduced from baseline over 12 months with DFX (–497.5 ng/mL, P=0.004 vs baseline) and PHL (–901.8 ng/mL, P