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Thalassemia is a group of genetically inherited hemoglobin (Hb) disorders characterized by reduced synthesis of the b-globin chain and a sub-sequent imbalance in the a/b-globin chain ratio that results in chronic hemolytic anemia. The severity of clinical phenotype is used to distinguish this heterogeneous disease in two main subtypes: Thalassemia Major (TM) and Thalassemia Intermedia (TI). Iron overload is mostly due to increased intestinal absorption because of chronic anemia. Transfusions, in contrast with what happens in TM, have a minor role in the development of iron overload. However, although 1-year data from the phase 2, prospective, randomized, double-blind, placebo-controlled trial and 1-year extension results from the THALASSA study assessing the efficacy and safety of deferasirox in TI patients with iron overload have been reported, no data, during randomized trials, have been so far published on Deferiprone (DFP) treatment (Taher et al Blood 2012 and Ann Hematol 2013) Adult patients with TI were randomly assigned in permuted blocks of 10 with a ratio 1:1 to DFP at 75 mg/kg/day for 7 d/week divided into three oral daily doses (DFP-group) or DFO by sc infusion (8–10 h) at 50 mg/kg per day for 5 d/week (DFO-group). The study was designed to detect an improvement in decreasing mean serum ferritin levels in each of the treated-groups from the initiation of therapy to each year (from year 1 to year 5) with a significance level of 5% and 80% power. The planned number of subjects was between 40 and 100 (Rochon Biometrics 1991). The primary endpoint was the treatment efficacy evaluated as change from the baseline value in serum ferritin levels during the 5 years assessed using a linear mixed-effects model (LMM, Laird-Ware Biometrics 1982) where we assumed the patient effect (given by the intercept terms for each patient) as random effect, while the treatment effect (treat), the time effect (time), the treatment-by-time interaction effect (treat×time), and the total transfusions in ml (tot TX) as fixed effects. Secondary endpoints were safety and survival analysis at 5-years evaluated considering the number of advers events and Kaplan-Meir curves respectively. Overall 88 patients, observed at 12 SoSTE centers in Italy between January 2001 and May 2011, were randomized (47 DFP-group and 41 DFO-group). There were no differences observed at baseline between the two randomized groups in clinical and haematological findings. The regression coefficient of time suggested that there was a linear decrease over time in the mean serum ferritin levels in both treatment-groups even if the p-value was very close to the statistical significance (Coeff. -88.4, 95% CI (-182.4; 5.6), p-value =0.065). However, the mean serum ferritin levels did not seem to be significantly different between the two treatment-groups over time (Coeff. -77.4, 95% CI (-231.7; 77.1), p-value=0.326 ). The effect of total blood transfusion on serum ferritin levels was not statistically significant (Coeff. 0.06, 95% CI (-0.01; 0.1), p-value=0.100). The estimated profiles of serum ferritin levels in the two groups were represented in Figure I. Agranulocytosis was reported in 4 case of DFP versus no cases of DFO group, respectively (p-value=0.118). Neutropenia was statistically significant different between the two groups DFP (6 (12.5%) versus no cases in DFO , p-value=0.027). Kaplan-Meier survival probability curves for the two treatment groups are shown in Figure II, and the log-rank test did not show any statistically significant difference in the survival between the two groups (p-value=0.36). In conclusion, these findings suggest as DFP shows same effectiveness and survival probability versus DFO with controlled safety profile. Therefore, these results support the possibility of using this drug in TI patients in which DFO and Deferasiorx is contraindicated. Figure I: Estimated profiles of the mean serum ferritin in the two treatment-groups from the fitted linear mixed-effects model. Figure I:. Estimated profiles of the mean serum ferritin in the two treatment-groups from the fitted linear mixed-effects model. Figure II. Kaplan–Meier survival probability curves in the two treatment groups during multi-center TI clinical trial (DFP: continous line; DFO: dashed line), (p-value=0.36). Figure II. Kaplan–Meier survival probability curves in the two treatment groups during multi-center TI clinical trial (DFP: continous line; DFO: dashed line), (p-value=0.36). Disclosures No relevant conflicts of interest to declare.

Epidemiologic as well as clinical studies confirm a close link between diabetes mellitus (DM) and heart failure (HF) in the general population. In a retrospective historical thalassemia major (TM) cohort, DM was demonstrated to lead to an higher frequency of cardiac complications also independently of cardiac iron status, but not prospective data are available. So, we determined prospectively the predictive value of DM for HF, arrhythmias and cardiac complications (HF, arrhythmias and pulmonary hypertension) in TM. We followed prospectively 537 patients enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) network. Fifty-six patients were excluded because a cardiac complication was present at the time of the first Cardiovascular Magnetic Resonance (CMR), representing our starting point. All the considered 481 TM patients were white (29.48±8.93 years, 263 females). Mean follow-up was 57.91±18.23 months. DM was present in the 9.8% of patients. Cardiac events were recorded in 36 patients (7.5%). There were 18 episodes of HF, 16 arrhythmias and 2 pulmonary hyperthension. DM was a significant predictive factor for HF (hazard ratio-HR=5.62, 95%CI=2.08-15.22; P DM remained a significant prognosticator for HF and cardiac complications also in a multivariate model including cardiac iron. In conclusion, DM was found to be a strong predictor for HF, arrhythmias and cardiac complications. Our findings are relevant for the prevention of glucose disorder metabolism and they stress the need to intensify the chelation therapy in patients in whom excess pancreatic iron is found by MR, where available, or when patients develop glucose metabolism disorders. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction. ACE-536, a recombinant fusion protein containing modified activin receptor type IIB and IgG Fc, is being developed for the treatment of anemias due to ineffective erythropoiesis (IE), such as beta-thalassemia (β-thal). In β-thal, IE is due to intracellular α-globin aggregates causing premature death of late-stage erythroid precursors. Patients with β-thal often have elevated levels of EPO and are unresponsive to erythropoiesis-stimulating agents (ESAs). ACE-536 binds to ligands in the TGF-β superfamily, such as GDF11, and promotes late-stage erythroid differentiation via a mechanism distinct from ESAs. In a healthy volunteer study, ACE-536 was well-tolerated and increased hemoglobin (Hb) levels (Attie K et al., Am J Hematol 2014). Murine ACE-536 (RAP-536) increased Hb levels and decreased RBC inclusion bodies and hemolysis in a mouse model of β-thal (Suragani R et al., Blood 2014). Aims. This is an ongoing, phase 2, multicenter, open-label, dose-finding study to evaluate the effects of ACE-536 in adults with transfusion-dependent (TD, defined as ≥4 units RBCs/8 weeks prior to baseline) or non-transfusion dependent (NTD, defined as Methods. Inclusion criteria included age ≥ 18 yr and anemia, defined as either being TD patient or having baseline Hb Results. Preliminary data were available for the 30 patients (23 NTD/7 TD) enrolled in the first 5 cohorts as of 18 Jul 2014. Median age was 34.5 yr (range: 20-57 yr), 16 (53%) were male and 83% had prior splenectomy. Mean (SD) baseline Hb for the NTD patients was 8.3 (0.9) g/dL. Efficacy data for the NTD patients in the 0.6 to 1.0 mg/kg cohorts demonstrated a maximum increase from baseline in Hb ≥ 1.5 g/dL in 7 of 11 (64%) patients. Efficacy data for the 7 TD patients treated in the 0.6 to 1.0 mg/kg cohorts demonstrated a >50% reduction in transfusion burden for all 7 patients. This was accompanied by a maximum decrease from baseline in serum ferritin levels ranging from 12-60%. Reductions in liver iron concentration by MRI were observed in both NTD and TD patients. Two patients with long-standing leg ulcers at baseline (one NTD, one TD) healed within approximately 3 months of ACE-536 treatment. ACE-536 was generally well tolerated. No related serious adverse events have been reported to date. The most frequent related adverse events included bone pain, headache and myalgia. No notable changes in platelets or WBC were observed. Conclusions. Based on preliminary data, ACE-536 administered SC every 3 weeks for up to 5 doses increased Hb levels in NTD patients and decreased transfusion requirement and serum ferritin levels in TD patients with β-thalassemia via a novel mechanism of action, and demonstrated a favorable safety profile. These data strongly support further evaluation of ACE-536 in patients with β-thalassemia. Disclosures Piga: Acceleron Pharma: Research Funding; Celgene: Honoraria; Novartis: Research Funding; ApoPharma: Research Funding. Voskaridou:Celgene Coporation: Membership on an entity's Board of Directors or advisory committees. Condon:Acceleron Pharma: Employment, Equity Ownership. Wilson:Acceleron Pharma: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership. Attie:Acceleron Pharma: Employment, Equity Ownership.

A case of gastrointestinal hemorrhage, associated with abdominal pain, in an 8-year-old child because of an arterial malformation of duodenum is reported. Selective arteriography showed the presence of an aneurismatic lesion of superior pancreaticoduodenal artery. The leakage of the vascular lesion during examination permitted the embolization by microcoils and cyanoacrylate glue. The follow-up by computed tomography scan revealed a complete occlusion of the lesion.

A multicenter randomized open-label long-term sequential deferiprone–deferoxamine (DFP-DFO) versus DFP alone trial (sequential DFP-DFO) performed in patients with thalassemia major (TM) was retrospectively reanalyzed to assess the variation in the left ventricular ejection fraction (LVEF) [1].

Background Cardiovascular Magnetic Resonance (CMR) by late gadolinium enhancement (LGE) allows to detect myocardial fibrosis. Myocardial fibrosis was shown to be a relative common finding in large cohort of Italian thalassemia major (TM) patients mainly related to HCV infection, but specific studies involving only pediatric patients are not available. Our aim was to investigate the prevalence and clinical-instrumental correlates of myocardial fibrosis in pediatric TM patients.

5 years after a previous study, we followed up a group of thalassemic patients, determining DHEA-S levels in peripubertal age, with the aim of evaluating whether adrenarche maturation occurred in boys and advanced in girls. Furthermore, we evaluated the degree of bone mineral density (BMD SDS(BA)) and analyzed growth parameters calculating standard deviation score with respect to bone age (BA) of height (Ht SDS(BA)), sitting height (SH SDSBA), and subischial leg length (SLL SDSBA), body mass index (BMI) and the difference between the values of the previous and the present study (deltaBMI), thyroid function and serum markers of bone metabolism. Our results showed persistent lack of adrenarche (DHEA-S 25+/-9.5 microg/dl) in all 6 boys and the absence of pubertal signs at chronological age (CA) of 12.4+/-1.4 yr and BA of 11.1+/-1.1 yr. Only one boy, 6 months later, showed a testicular volume of 4 ml (Tanner stage G2) with an increase of DHEA-S value (181 microg/dl) at BA 12.8 yr. Body disproportion and severe degree of osteopenia (BMD SDSBA -2.41+/-0.5) were observed in all boys, even though Ht SDSBA (0.14+/-0.8) and markers of bone metabolism were within the normal range. No change in nutritional status was observed (deltaBMI 0.09+/-0.4 kg/m2). In contrast, all the thalassemic girls had DHEA-S values (172.7+/-97.7 microg/dl) within the normal range at BA 12.7 +/-0.6 yr that was similar to CA. Furthermore, the appearance of Tanner stage B2 occurred in each of them at BA, near to CA, of 10.4+/-0.9 yr, and menarche was observed in three of them at mean BA, near to CA, of 11.4+/-0.9 yr. Ht SDSBA was below normal range (-1.11+/-0.8), but SLL SDSBA and SH SDS(BA) values were reduced homogeneously, so that proportional body growth was observed. A significant change in nutritional status was observed (deltaBMI 2.69+/-0.9 kg/m2). Bone density value (BMD SDS(BA) -0.25+/-0.4) was in the normal range. There were no statistically significant differences between boys and girls for ferritin serum levels, blood consumption and desferrioxamine dosage. In conclusion, lack of change in nutritional status, measurable in the form of deltaBMI, but not BMI alone, considered an important physiological regulator of adrenarche, regardless of individual adrenal androgen secretion, could have a key role in the lack of adrenarche persisting in thalassemic boys during peripubertal age. Further follow up is necessary, in particular when boys reach puberty, because delayed adrenarche represents the most intriguing aspect in these patients.

A retrospective analysis of time series of hemoglobin (Hb) destruction of 24 children (11 males and 13 females) with thalassemia from the age of 6 to 12 years showed that the Hb destruction rate typically oscillated with an average period of 50 days. A possible relation between the periodism and the severity of the disease is also suggested.

UNLABELLED It is known that in thalassemic patients there is a disproportion between lower and upper segments whose causes have not yet been identified. We evaluated whether the administration of estrogens to induce puberty in hypogonadic thalassemic girls caused an inappropriate acceleration of bone maturation and whether this had a negative influence on final and sitting height. MATERIALS AND METHODS Twelve thalassemic patients with spontaneous puberty (Group A) and seven patients with hypogonadism (Group B) were studied. The mutations of the beta gene were identified by DNA analysis. We took into account four observations, ranging from the onset of spontaneous puberty in group A or the start of substitutive therapy in group B, to 5 years later. At each observation we considered: chronological age (CA), bone age (BA), height (Ht) expressed in cm and as standard deviation score (HtSDS) calculated with respect to CA (HtSDSCA) and BA (HtSDSBA), growth spurt, sitting height, expressed as SDS (SH-SDS), and height gain (HG). The delta BA and delta CA were calculated between the first and the final observation values to evaluate the bone age acceleration (delta BA/delta CA). RESULTS No acceleration of BA was noted. delta BA/delta CA was 0.98 +/- 0.1 in group A and 0.89 +/- 0.1 in group B (p > 0.05). All patients in group B had the most severe form (beta degree/beta degree) of thalassemia. During the final observation, SH-SDS was -1.43 +/- 1.2 and -2.9 +/- 0.6 in group A and B respectively (p < 0.002), while no difference between the two groups for HtSDSCA and HtSDSBA was observed. HG was greater in group A than in group B (17.7 +/- 5.4 cm vs 10.8 +/- 5.2 cm) (p < 0.002), such as the spurt 8.6 +/- 1.4 cm (group A) and 6.1 +/- 2.6 cm (group B) (p < 0.05). CONCLUSIONS Girls with hypogonadism did not show an inappropriate acceleration of BA, as they reached near final height similar to girls with spontaneous puberty. The auxological parameters showed a more severe body disproportion with the prevalence of the lower segment in the hypogonadic girls. This could be explained by a higher degree of bone marrow hyperplasia related to the most severe form of thalassemia and a higher blood consumption. As a consequence, damage at the vertebral level might determine an inability of the bone tissue to respond to estrogens. We suggest beginning estrogen therapy earlier in order to obtain better truncal growth.

The changes in bone mineral density (BMD) measured by single photon absorptiometry (SPA) using two observations conducted over a period of 2 years were examined in 54 thalassemic subjects [30 F(A) and 24 M(B)] with a chronological age ranging from 2.6 to 22.6 years and in 27 sex- and age-matched controls (C). Each category (A, B and C) was divided into three groups according to pubertal signs: pre-pubertal subjects (A1, B1 and C1); peri-pubertal subjects (A2, B2 and C2) and pubertal subjects from the first observation (A3, B3 and C3). Furthermore, each group of patients was divided into sub-groups on the basis of haematological phenotypes, those with a more severe form were called beta0/beta0 while those with other forms were called "others". The most significant findings were the following: the presence of a more severe reduction of the bone mineral density in patients with the beta0/beta0 phenotype than in patients with the "others" phenotype; patients with hypogonadism corresponded to the beta0/beta0 phenotype, while those with spontaneous puberty corresponded to the "others" phenotype. In conclusion, since puberty and the degree of bone mineral density are related to the haematological phenotype, puberty (spontaneous or induced) positively influences the bone mineral density only at the start of puberty, while subsequently, the degree of osteoporosis is the expression of widespread and chronic systemic damage due to the haematological phenotype.

Although the heart and liver have traditionally been the organs of interest for iron-related complications in Thalassemia Major (TM), endocrine disorders are common and carry significant morbidity. This is thought to result from iron accumulation in multiple organs functioning as part of endocrine systems. Deferasirox chelation therapy is well tolerated in TM and reduces iron burden effectively in the heart and liver. The impact of deferasirox on endocrine parameters remains unclear. The aim of this study was to examine the long-term efficacy of deferasirox for both the prevention of endocrine dysfunction in patients free of endocrine complications, and in improving endocrine parameters in those with pre-existing endocrine disorders. This was a multicentre retrospective cohort study of TM patients over 2 years of age receiving chelation treatment with once daily oral deferasirox monotherapy. Data on relevant clinical and laboratory parameters, including glycaemia, bone mineral density (BMD) z-scores, and testing of the pituitary, gonadal, thyroid and adrenal axes were collected at baseline and follow-up. Dosing regimens were titrated according to standard practice and only patients treated for at least 3 years were included in the present analysis. Data are presented as mean with standard deviation unless otherwise stated. Statistical comparisons were made using paired t-tests for continuous data, and chi-square test or Fisher's exact test to compare categorical data distributions. A total of 72 patients (69% female) with a mean age 26 ± 15 years were included. Mean duration of exposure to deferasirox was 6.9 ± 2.7 years with a mean daily dose of 25 ± 5 mg/kg. Myocardial T2* significantly increased from baseline to follow up (29.30 ± 10.29ms vs. 33.5 ± 13.06ms, P=0.01), signifying effective removal of iron from the heart. Among patients free of thyroid dysfunction at baseline, we observed no significant difference in mean TSH (2.10 ± 1.00 mi/u/ml vs. 2.28 ± 1.06 mi/u/ml, P=0.23 ), FT4 (6.89 ± 4.50 ng/ml vs. 7.10 ± 4.71 ng/ml, P=0.34) or FT3 (2.87 ± 1.16 pg/ml vs. 3.00 ± 0.58 pg/ml, P=0.35) during the study period. Of 9 patients with biochemical hypothyroidism at baseline, including 4 receiving thyroxine, we observed no significant change in thyroid function tests or thyroxine requirements. Two new incidences of subclinical hypothyroidism were noted. Among patients free of diabetes mellitus at baseline, we observed no significant variation in blood glucose measurements (pooled over 3 consecutive readings) at the end of treatment (88.62 ± 10.53 mg/dl vs. 88.36 ± 9.35 mg/dl, P=0.83). There was 1 incidence of type 2 diabetes during the study period. No significant difference was seen in blood sugar control or insulin requirements between baseline and end of treatment in patients with type 1 diabetes. Excluding normal pre-pubertal paediatric patients, there was no significant increase in the prevalence of hypogonadism between baseline and the end of study, 21 patients (38%) vs. 24 (44%) were diagnosed with hypogonadism respectively (P=0.56). Biochemical indices of bone metabolism showed no significant difference in calcium levels or vitamin D from baseline to follow up. BMD was improved from baseline to follow-up, with normal Z scores in 7 (20%) patients, 20 (57%) osteopenic, and 8 (23%) osteoporotic, compared with 7 (20%), 24 (69%), and 4 (11%) at end of treatment, respectively. Adverse effects were infrequent and of low grade, effecting 7 (9.7%) patients. Endocrine disorders are common sequelae of iron overload in patients with TM, and follow an insidious course of progressive dysfunction. We report infrequent development and progression of endocrine abnormalities, and significant improvement in bone density in TM patients treated with deferasirox over a 7-year follow-up period. In comparison with the incidence of complications from other studies of TM, deferasirox appears effective in reducing risk of developing endocrine disorders. Increasing myocardial T2* values confirmed effective removal of iron from the heart. Although multiple biological pathways are likely responsible, reduction in global iron alleviating siderosis of endocrine organs may be responsible for preserved function and bone mineral metabolism. Our study suggests that chelation therapy with deferasirox may prevent endocrine complications in patients with TM and prevent progression in those with established abnormalities Disclosures: Silverio: Novartis: Consultancy, Research Funding.

Introduction It is still controversy in thalassemia major (TM) if Cardiovascular Magnetic Resonance (CMR) T2* screening should be initiated before the 10 years. To answer this question, we studied retrospectively the prevalence of cardiac iron and function and myocardial fibrosis by CMR in a consistent cohort of TM patients younger than 10 years. Methods From the 2171 patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network, we retrospectively selected the 35 TM patients aged less than 10 years who had undergone at least one MRI scan. Myocardial iron overload (MIO) was measured by T2* multislice multiecho technique. Biventricular function parameters were quantitatively evaluated in a standard way by cine images. To detect myocardial fibrosis, late gadolinium enhancement images were acquired. Results Patients’ age ranged from 4.2 to 9.7 years. All MRI scans were performed without sedation. Nine patients (25.7%) showed no myocardial iron overload (MIO),22 patients (62.9%) showed an heterogeneous MIO with a T2* global value ≥ 20 ms; 2 patients (5.7%) showed an heterogeneous MIO and a T2* global value < 20 ms and 2 patients (5.7%) had a homogeneous MIO. No patients showed myocardial fibrosis. Table 1 reports the data of the 4 patients (3 males and 1 female) with significant myocardial iron overload (global heart T2* < 20 ms). The youngest was 6 years old, all showed no heart dysfunction and in all the iron transfused was less than 35 g. Conclusion The first cardiac T2* assessment should be performed as early as possible without sedation and it is mandatory whenever poor compliance is suspected or if chelation has been started late. The use of the contrast medium to detect myocardial fibrosis can be postponed until after 10 years of age. A more sensitive segmental approach to detected heart iron should be considered. Therapy can be modified on the basis of the MRI results and serious organ damage can be prevented. Disclosures: No relevant conflicts of interest to declare.

Background: Due to the limited data available in literature, the aim of this multi-centre study was to prospectively compare in thalassemia major (TM) patients the efficacy of combined deferiprone (DFP) and deferoxamine (DFO) regimen versus either DFP and DFO in monotherapy by cardiovascular magnetic resonance (CMR) over a follow up of 18 months. Methods: Among the first 1135 TM patients in the MIOT (Myocardial Iron Overload in Thalassemia) network, we evaluated those who had received either combined regimen (DFO + DFP, N=51) or DFP (N=39) and DFO (N=74) monotherapies between the two CMR scans. Iron overload was measured by T2* multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images. Results: The percentage of patients that maintained a normal global heart T2* value was comparable between DFP+DFO versus both monotherapy groups. Among the patients with myocardial iron overload at baseline, the changes in the global heart T2* and in biventricular function were not significantly different in DFP+DFO compared with the DFP group. The improvement in the global heart T2* was significantly higher in the DFP+DFO than the DFO group, without a difference in biventricular function. Among the patients with hepatic iron at baseline, the decrease in liver iron concentration values was significantly higher with combination therapy than with either monotherapy group. Conclusions: In TM patients at the dosages used in the real world, the combined DFP+DFO regimen was more effective in removing cardiac iron than DFO, and was superior in clearing hepatic iron than either DFO or DFP monotherapy. Combined therapy did not show an additional effect on heart function over DFP.

In order to evaluate whether changes of adrenal steroid serum levels occurring during the prepubertal period influence the degree of osteopenia, dehydroepiandrosterone sulfate (DHEAS) was longitudinally monitored as marker of the onset of adrenarche. Fifteen thalassemic patients, 9 girls (Group 1) and 6 boys (Group 2), with chronological age (CA) from 6.1 to 10.3 years and bone age (BA) from 6 to 9.6 years, were studied. Two observations, 14 months apart, were made. All patients had no pubertal signs according to Tanner during the period of observation, and auxological data (height, BMI and height velocity) were evaluated in respect to bone age. There was a statistically significant difference between the two groups for serum DHEAS, BGP serum levels, height velocity and bone mineral density expressed as standard deviation score (BMDsds) in respect to both bone age and height age (the latter was calculated in order to eliminate the influence of height on BMD). Alterations of bone metabolism were excluded by determination of calcium, phosphorus, alkaline phosphatase activity, parathormone, 25-OH-D3, IGF-I serum levels, all these values being normal. In conclusion, our data show that a delayed adrenarche occurs in thalassemic boys which is correlated with a severe degree of osteopenia, even though the relationship between them is not yet established.

Hypothyroidism is one of the most frequent endocrinological complications in thalassemic patients [1]. Lack or delay of puberty [2-4], hypoparathyroidism [5], and insulin-dependent diabetes mellitus [6] are concomitant endocrine abnormalities in such patients. It is reported in the literature that these complications are due to iron over load at the hypothalamic and/or pituitary level and/or at the glandular level [7-9]. Nevertheless, the cause of hypothyroidism in thalassemic patients is unclear still in fact, the results presented in the literature show a broad spectrum of possible alterations [6, 9].

Abstract 3190 Introduction: Cardiac complications mainly related to myocardial iron overload (MIO) remain the main cause of morbidity and mortality in thalassemia major (TM). Thalassemia cardiomyopathy is treatable and partly reversible if appropriate chelation therapy is instituted in time. The validated multislice multiecho T2* Cardiovascular Magnetic Resonance (CMR) technique has permitted to quantify segmental and global myocardial iron burden detecting different patterns of iron overload. The aim of this study was to verify the risk of cardiac complications related to different patterns of MIO in a large cohort of TM patients. Methods: We considered 812 TM patients for who CMR and cardiac data were collected in a central data base. Three short-axis views (basal, medium, apical) of the left ventricle were acquired using a multislice multiecho T2* sequence. Using a previously validated software the 16 segmental T2* values and the mean global heart T2* value were provided. A conservative cut off of 20 ms was considered the limit of normal for the segmental and global T2* values. Results: We identified 4 groups of patients: group I (17%) with homogeneous MIO (all segments with T2* Conclusions: Homogeneous MIO predicts a significantly higher risk to develop cardiac complications, especially heart failure, suggesting an intensive chelation therapy in this group of patients. Disclosures: No relevant conflicts of interest to declare.

Abstract 5298 Introduction: Magnetic Resonance (MR) is the unique non invasive suitable technique to evaluate quantitatively the changes in cardiac and hepatic iron and in cardiac function in thalassemia major (TM) patients under different chelation regimens. This study aimed to prospectively assess the efficacy of the sequential deferiprone–deferrioxamine (DFP-DFO) versus deferiprone (DFP) and deferrioxamine (DFO) in monotherapy in a large cohort of TM patients by quantitative MR. Methods: Among the first 1135 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network, 392 patients performed a MR follow up study at 18±3 months. We evaluated prospectively the 35 patients treated with DFP-DFO versus the 39 patients treated with DFP and the 74 patients treated with DFO between the 2 MR scans. Iron concentrations were measured by T2* multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images. Results: Excellent/good levels of compliance were similar in the DFP-DFO (97.1%) versus DFP (94.9%) and DFO (95.9%) groups. No significant differences were found in the frequency of side effects in DFP-DFO (15.6%) versus DFP group (9.4%). The percentage of patients who maintained a normal global heart T2* value (≥20 ms) was comparable between DFP-DFO (96%) versus DFP (100%) and DFO (98.1%) groups. Among the patients with myocardial iron overload (MIO) at baseline (global heart T2* Among the patients with hepatic iron at baseline (T2* Conclusions: Prospectively we did not find significant differences on cardiac and hepatic iron or in cardiac function in TM patients treated with sequential DFP–DFO therapy versus the TM patients treated with DFO or DFP in monotherapy. Disclosures: Pepe: Novartis: Speakers Bureau; Apotex: Speakers Bureau; Chiesi: Speakers Bureau. Off Label Use: Association of two chelators commercially available in order to obtain a higher efficacy. Lai:Novartis: Honoraria, Research Funding.

Abstract 1087 Introduction: No data are available in literature about possible different changes in cardiac and hepatic iron and in cardiac function in thalassemia major (TM) patients treated with sequential deferipron–desferrioxamine (DFP-DFO) versus deferasirox (DFX). Magnetic Resonance (MR) is the unique non invasive suitable technique to evaluated quantitatively this issue.Our aim was to prospectively assess the efficacy of the DFP-DFO vs DFX in a large cohort of TM patients by quantitative MR. Methods: Among the first 1135 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network, 392 patients performed a MR follow up study at 18 ± 3 months according to the protocol. We evaluated prospectively 35 patients treated with DFP-DFO versus 80 patients treated with DFX between the 2 MR scans. Cardiac iron was evaluated by T2* multiecho multislice technique. Biventricular function parameters were quantitatively evaluated by cine images. Liver iron was measured by T2* multiecho technique. Results: Excellent/good levels of compliance were similar in the two groups (DFP-DFO 97.1% vs DFX 98.8%; P=0.544). Among the patients with no significant myocardial iron overload (MIO) at baseline (global heart T2*≥20 ms), there were no significant differences between groups to maintain the patients without myocardial iron overload (DFP-DFO 96% vs DFX 98%; P=0.536). Among the patients with MIO at baseline, in both groups there was a significant improvement in the global heart T2* value (DFP-DFO: 4.8±3.9 ms P=0.004 and DFX: 3.5±4.7 P=0.001) and a significant reduction in the number of pathological segments (DFP-DFO: −3.2±3.8 P=0.026 and DFX: −2.4±3.8 P=0.003). Only in sequential group there was a significant increment in the left and right ventricular ejection fractions (4.3±5.1% P=0.035 and 6.7±6.6% P=0.017, respectively). The improvement in the global heart T2* was not significantly different between groups. The improvement in the left as well in the right ventricular ejection fractions was significantly different between groups (P=0.009 and P=0.015, respectively) (Figure 1). Among the patients with hepatic iron at baseline (T2* Conclusions: In TM patients prospectively no significant differences on cardiac iron were found between sequential DFP–DFO treatment versus DFX in monoterapy, although the DFP-DFO treatment was significantly more effective in improving biventricular global systolic function. Conversely, DFX was significantly more effective in reducing hepatic siderosis. Disclosures: Pepe: Novartis: Speakers Bureau; Apotex: Speakers Bureau; Chiesi: Speakers Bureau. Off Label Use: Association of two chelators commercially available in order to obtain a higher efficacy. Borgna-Pignatti:Apotex: Honoraria; Novartis: Honoraria, Research Funding.

Abstract 3194 Introduction: Using T2* Magnetic Resonance (MR) a randomized placebo controlled study from Sardinia demonstrated combination therapy with deferiprone and desferrioxamine (DFP+DFO) significantly more effective than DFO in improving myocardial iron. One non-randomized study from Sardinia and one observational study from Greece seem to confirm for DFP+DFO therapy the most rapid clearance of cardiac iron. No data are available in literature about prospective comparisons on cardiac iron and function and liver iron in TM patients treated with DFP+DFO versus DFP and DFO in monotherapy. The aim of our multi-centre study was to assess prospectively in a large clinical setting the efficacy of the DFP+DFO versus DFP and DFO in TM patients by quantitative MR. Methods: Among the 1135 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network we selected those with an MR follow up study at 18±3 months who had been received one chelator alone between the 2 MR scans We evaluated prospectively the 51 patients treated with DFP+DFO versus the 39 patients treated with DFP and the 74 patients treated. Iron overload was measured by T2* multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images. Results: The dosages were: combined therapy DFP 61.9±24.3 mg/kg per 6.1±1.4 days/week and DFO 40.7±6.0 per 3.5±1.1 days/week; DFP 73±13 mg/kg per 6.1±1.4 days/week; DFO 40.7±6.5 per 5.4±0.93 days/week. Excellent/good levels of compliance were comparable in the DFP+DFO (90.2%) versus DFP (94.9%) and DFO (95.9%) groups. The percentage of patients who maintained a normal global heart T2* value (≥20 ms) was comparable between DFP+DFO (96%) versus (100%) and DFO (98.1%) groups. Among the patients with myocardial iron overload at baseline (global heart T2* Conclusions: Prospectively in TM patients at the dosages used in the clinical practice combined DFP+DFO showed superior reduction in myocardial iron only versus the DFO in monotherapy and it did not show better improvement in biventricular function in comparison to DFO and DFP monotherapy. On the other hand, combined DFP+DFO was significantly more effective in the reduction of the liver iron versus DFO and DFP in monotherapy. Disclosures: Pepe: Novartis: Speakers Bureau; Apotex: Speakers Bureau; Chiesi: Speakers Bureau. Off Label Use: Association of two chelators commercially available in order to obtain a higher efficacy.

Abstract 5302 Background: A multicentre randomized controlled trial (RCT) was designed to assess the effectiveness of long-term sequential deferiprone-deferoxamine (DFO-DFP) versus DFP alone to treat thalassaemia major (TM) (Maggio et al.,2009). Effectviness, survival, adverse events and costs were comparable between the groups. These findings were confirmed in a further 21-month follow-up (Pantalone et al., 2011). Moreover, deferiprone-alone has been reported to be superior to deferoxamine for the removal of cardiac iron and improvement in left ventricular ejection function (LVEF). However, little is known of its relative effect on LVEF after long-term treatment. Therefore, data from this prospective RCT were retrospectively analyzed to assess the LVEF responses to these treatments. Methods: In this retrospective survey of RCT, 99 patients with TM received, from September 30, 2000 to December 31, 2007, LVEF study consecutively (Table I). Generalized Estimating Equations (GEE) model was used to show the possible change of the mean of LVEF over the time between the Sequential DFP-DFO versus the DFP (Hedeker & Gibbons, 2006). This approach was implemented in the 'xtgee' procedure of Stata 11 software (StataCorp, College Station, TX, USA). All of the statistical analyses were performed under code at the Department for Mathematical and Statistical Sciences 'S. Vianelli', University of Palermo (Italy) by A.V. Results: Baseline findings are shown on Table I. Figure 1 shows the proÞles of the GEE model for the change in the mean LVEF between the two groups. The regression coefficient of treatment suggests as, the DFP-group shows statistically significant increase of mean ejection fraction over time (Coeff. 0,97, 95% CI (0,51; 1,44), p-value Discussion: Previous retrospective studies suggested as deferiprone –treated patients had higher LVEF in comparison with Deferoxamine (DFO) or Deferasirox (DFX) treated groups (Anderson et al., 2002; Pepe et al., 2011). Moreover, survival analysis suggested a substantial decline in cardiac deaths in recent years, related to switching high-risk patients from subcutaneous desferrioxamine to chelation regimes which include the oral chelator deferiprone (Borgna-Pignatti et al., 2006; Telfer et al., 2009). Finally, Pennell et al. 2006 suggested, during a RCT over 1 year comparing DFO versus DFP, as LVEF increased significantly more in the deferiprone-treated group (3.1% vs 0.3% absolute units; P =.003). This retrospective survey of long-term prospective RCT, shows as the effect of deferiprone-alone treatment increases significantly during the years (Coeff. 0,97, 95% CI (0,51; 1,44), p-value Disclosures: Off Label Use: Deferiprone on sequencial way with Deferoxamine.

Abstract 4259 Introduction: Most deaths in thalassemia major (TM) result from cardiac complications due to iron overload. No data are available in literature about possible different changes in cardiac and liver iron in TM patients treated with sequential deferipron–deferoxamine (DFP-DFO) versus deferipron (DFP) and deferoxamine (DFO) in monotherapy. Magnetic Resonance (MR) is the unique non invasive suitable technique to evaluate quantitatively this issue. The aim of this multi-centre study was to assess prospectively in the clinical practice the efficacy of the DFP-DFO versus DFP and DFO in monotherapy in a cohort of TM patients by quantitative MR. Methods: Among the first 739 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network, 253 patients performed a MR follow up study at 18 ± 3 months according to the protocol. We evaluated prospectively the 25 patients treated with DFP-DFO versus the 30 patients treated with DFP and the 66 patients treated with DFO between the 2 MR scans. Myocardial and liver iron concentrations were measured by T2* multislice multiecho technique. Results: The doses of the sequential treatment were DFP 70±14 mg/kg/d for 4 d/w and DFO 42±8 mg/kg/d for 3 d/w, the dose of DFP was 73±16 mg/kg/d, DFO was 41±7 mg/kg/d for 5.5 d/w. Excellent/good levels of compliance were similar in the 3 groups (DFP-DFO 96% versus DFP 97% versus DFO 92%; P = 0.67). Among the patients with no significant myocardial iron overload at baseline (global heart T2* ≥ 20 ms), there were no significant differences between groups to maintain the patients without myocardial iron overload (DFP-DFO 95% versus DFP 100% versus DFO 100%; P = 0.23). Among the patients with myocardial iron overload at baseline (global heart T2* < 20 ms), only DFP and DFO showed a significant improvement in the global heart T2* value (P = 0.001 and P = 0.003, respectively) and in the number of segment with a normal T2* value (P = 0.031 and P = 0.0001, respectively). The improvement in the global heart T2* was significantly different among groups (mean difference global heart T2* DFP-DFO 2.2 ± 4.1 ms, DFP 10.7 ± 7.2, DFO 3.6 ± 5.4; P = 0.007). The improvement in the global heart T2* was significantly lower in the DFP-DFO versus DFP group (P =0.014), but it was not significantly different in the DFP-DFO versus the DFO group (P = 0.63) (see the figure). In patients with liver iron overload at baseline (liver T2* < 5.1 ms), the change in the liver T2* was not significantly different among groups (mean difference liver T2* DFP-DFO 0.9 ± 2.1 ms, DFP 2.3 ± 5.8, DFO 2.9 ± 4.9; P = 0.58). Conclusions: prospectively in a clinical setting over 15 months we did not find significant differences on cardiac and liver iron in TM patients treated with sequential DFP–DFO versus the TM patients treated with DFO. Conversely, DFP monotherapy was significantly more effective than DFP-DFO in improving myocardial siderosis. Disclosures: No relevant conflicts of interest to declare.

Prognosis of thalassemia major patients has dramatically improved in the past two decades. Previous papers, including retrospective and prospective non-randomised clinical trials, suggested that mortality, due mainly to cardiac damage, was less or completely absent in patients treated with DFP alone or with associated chelation treatment. For this reason, the main aim of this study was to evaluate whether the addition of deferiprone treatment was also associated with a mortality decrease among a large randomised cohort of thalassemia major patients. Survival analysis was performed among 264 thalassemia major patients assessed for eligibility from 09/30/2000 to 01/31/2008, during a long-term multicentre randomised clinical trial. The reported chelation therapies included sequential DFP-DFO, associated DFP and DFO, DFP and DFO interventions. The survival curves were compared by gender and treatment groups using the long-rank test. Cox regression models were used to explore association between risk for death among treatments and survival time. All statistical analyses were performed by STATA 9.2. All these patients performed DFO before the date of randomisation. One death was due to a graft versus host disease (GVHD) in a patient underwent bone marrow transplantation and this patient was censored at the time of transplant. The improved survival for sequential DFP-DFO, DFP-alone, and associated DFP-DFO treated patients versus DFO-treated was statistically significant (log-rank test, χ2= 18.64; p≤0.01). In fact, no deaths were reported during DFP-alone and DFP-DFO associated treatments along a 564.5 person-years period of observation. Only one death was reported during DFP-DFO sequential treatment in a patient who had experienced 1-year before an episode of heart failure. All other ten deaths were among patients under DFO treatment. The hazard ratio for death of DFO treatment versus other treatments was 27.78 (p= 0.002). The main factors correlated with increased hazard ratio for death were cirrhosis, arrhythmia, previous episode of heart failure, diabetes, hypogonadism, hypothyroidism. No correlation between serum ferritin levels and hazard ratio for death was found. These results confirm as deferiprone alone or in addition to deferoxamine intervention is able to reduce mortality in thalassemia major patients probably because of its specific cardioprotective effect occurring independently from body iron overloading

Cardiovascular Magnetic Resonance (CMR) by delayed enhancement (DE) has proven to visualize myocardial scarring, but no dedicated studies are available in thalassemia major. Aim of our study was to investigate the prevalence, extent, clinical and instrumental correlates of myocardial fibrosis or necrosis by DE CMR in thalassemia major patients. CMR-DE was performed in 115 thalassemia major patients. Myocardial iron overload was determined by multislice multiecho T2*. Cine images were obtained to evaluate biventricular function. All patients gave written informed consent to the protocol. The project was approved by the institutional ethics committee. DE areas were present in 28 patients (24%). Extent of DE was 3.9±2.4 %. In 26 patients the location of fibrosis was not specific and patchy distribution was prevalent. Two patients showed transmural DE following coronary distribution. The DE group was significantly older (P=0.004). DE correlated with cardiac risk factors (P=0.01), history of cardiac complications (P=0.001), anti-HCV antibodies (P = 0.04) and ECG-changes (P=0.002). We did not find significant relation of DE with heart T2* values and biventricular function. Figure shows a thalassemia major patient with no myocardial iron overload (all 16 segments T2* values > 20 ms) (A) and transmural DE (black arrows) following coronary distribution in the apical region (B,C). In conclusion, in thalassemia major patients the significant presence of myocardial fibrosis/necrosis seems to be a time dependent process correlating with cardiovascular risk factors and cardiac complications. HCV infection could be a causal agent in the pathogenesis of myocardial scarring. ECG-changes showed a good accuracy in predicting myocardial scarring. Figure Figure

Little is known about cardiac involvement in Thalassemia Intermedia (TI) using magnetic resonance imaging (MRI). Thus, we investigated myocardial and liver iron overload, myocardial fibrosis, biventricular function parameters and their inter-relationship in 60 TI using MRI. Then, we compared the data of 35 selected TI with age < 39 years with that of 60 Thalassemia Major (TM) patients matched for age. Myocardial Iron Overload (MIO) was assessed using a multislice multiecho T2* approach. Biventricular function parameters were measured quantitatively by cine images. Myocardial fibrosis was evaluated by late gadolinium-enhanced. MIO was present in the 22% of TI patients, more frequently (92%) with an heterogeneous distribution. TI patients with myocardial fibrosis (32%) showed significantly reduced left ventricular ejection fraction (LVEF) (P=0.01). No significant correlation was found between myocardial fibrosis and MIO. Figure shows a TI patient with no myocardial iron overload (all 16 segments and the mid-ventricular septum with T2* values > 20 ms) (A) and late enhancement (white arrows) in the antero-septal junction, in the infero-septal junction and in the mid-ventricular septum (B). In TI patients MIO was significantly lower respect to TM patients; conversely volumes, cardiac indexes, LVEF, bi-atrial areas, and liver iron overload were significantly higher. Myocardial fibrosis was comparable between the 2 groups. TI patients showed lower myocardial iron burden and more pronounced high cardiac output findings with myocardial fibrosis significantly associated to impaired heart function. These data seem to suggest using MRI also for TI patients and could place the basis to reconsider the current cardiological and haematological management in this population. Figure Figure

Three short-term randomised clinical trials suggested not difference of Deferiprone (L1) vs Deferoxamine (DFO) in term of iron overload efficacy in thalassemia major (TM) patients. To assess whether L1 (75mg/Kg) alone was comparable to a sequential treatment using L1 (75mg/Kg) for 4 days and DFO (50mg/Kg) for 3 days, we carried ahead a large long-term randomised clinical trial. One-hundred and forty consecutive patients with TM and serum ferritin between 1,500 and 3,000 ng/ml were randomly assigned to L1 (n°69) or sequential L1-DFO (n°71) and treated for 5 years. The main measure of efficacy was the reduction of serum ferritin levels. Secondary outcomes were liver and heart iron contents assessed by T2* magnetic resonance. After one year-treatment the mean serum feritin reduction was −105 ± 90.4 in L1 and −409 ± 64.2 in sequential L1-DFO treatment (p Fig. 1 VARIATIONS OF THE FERRITIN LEVELS DURING FIVE YEARS TREATMENT BETWEEN THE TWO ARMS OF THE TRIAL Fig. 1. VARIATIONS OF THE FERRITIN LEVELS DURING FIVE YEARS TREATMENT BETWEEN THE TWO ARMS OF THE TRIAL

Abstract 3197 Background: The prognosis for thalassemia major (TM) has dramatically improved in the last two decades. However, many transfusion-dependent patients continue to develop secondary iron overloading, and eventually death, particularly from cardiac disease. The possibility of detecting easily and earliest the patients at risk of cardiac death is so far the main challenge of clinical management of these patients. Therefore, the mean reduction of Left Ventricular Ejection Fraction (LVEF), determined by echocardiography, was evaluated over the time. Methods: Among the 413 observed patients only 188 had complete records for LVEF measurements during, at least, five considered consecutive years. Included patients were divided into two cohorts: the not alive and the alive-group with 22 and 166 patients, respectively. Generalized Estimating Equations (GEE) model was used to show the reduction of the mean of LVEF (Hedeker & Gibbons, 2006). This approach was implemented in the 'xtgee' procedure of Stata 11 software (StataCorp, College Station, TX, USA). The logistic regression model was used to evaluate the risk of death (Collet D. 2003). In this analysis, the mean reduction of LVEF was categorized into three levels: the baseline category including all patients with an increase greater than 0%, the category 1 including all patients with a reduction greater than 0% but less than 7% and the category 2 including all patients with a reduction higher or equal to 7%. All of the statistical analyses were performed under code at the Department for Mathematical and Statistical Sciences 'S. Vianelli', University of Palermo (Italy) by A.V. Results: Baseline findings are shown on Table I. Figure 1 shows the proÞles of the GEE model for the mean LVEF between the two groups. The regression coefficient of Status×Time shows a statistically significant linear decrease over the time of 1,51 per year of the mean LVEF between not alive versus alive patients (Coeff. −1.51, CI (−2,31;−0,71), p-value Discussion: Recently, Kirk et al. 2009 suggested as cardiac T2* magnetic resonance is able to detect patients at high risk of heart failure and arrhythmia from myocardial siderosis. However, other studies showed the presence of patients with abnormal heart function and normal heart T2* and did not suggest lower heart T2* for patients suffering from arrhythmia (Pepe et al., 2006; Marsella et al.,2011). Moreover, although the use of T2* is spreading, its availability is so far limited. Instead, availability of echocardiography is surely greater. Moreover, interobserver and intraobserver reliability for the visual assessment of the global LVEF measurements have been extensively shown even in comparison with Magnetic Resonace Imaging (Hoffmann et al. 2005; Gimelli et al. 2008; Blondheim et al., 2008; Sjzli et al. 2011). Therefore, repeated measurements of LVEF may be a strong and more accessible tool for detecting at risk of heart failure TM population. Disclosures: No relevant conflicts of interest to declare.

Chelation therapy with new drugs prevents cardiac damage and improves the survival of thalassemia patients. Liver diseases have emerged as a critical clinical issue. Chronic liver diseases play an important role in the prognosis of thalassemia patients because of the high frequency of viral infections and important role of the liver in regulating iron metabolism. Accurate assessment of liver iron overload is required to tailor iron chelation therapy. The diagnosis of hepatitis B virus– or hepatitis C virus–related chronic hepatitis is required to detect patients who have a high risk of developing liver complications and who may benefit by antiviral therapy. Moreover, clinical management of chronic liver disease in thalassemia patients is a team management issue requiring a multidisciplinary approach. The purposes of this paper are to summarize the knowledge on the epidemiology and the risks of transmission of viral infections, to analyze invasive and noninvasive methods for the diagnosis of chronic liver disease, to report the knowledge on clinical course of chronic viral hepatitis, and to suggest the management of antiviral therapy in thalassemia patients with chronic hepatitis B or C virus or cirrhosis.

Background. Luspatercept is a fusion protein (modified activin receptor IIB-IgG Fc) being investigated for the treatment of anemias with ineffective erythropoiesis. In beta-thalassemia, imbalanced production of alpha and beta globin chains in erythroid precursors inhibits late-stage erythroid differentiation, leading to anemia, ineffective erythropoiesis (IE), and dysregulated iron homeostasis. Luspatercept promotes late-stage erythroid differentiation, corrects ineffective erythropoiesis, and reduces alpha globin aggregates, hemolysis, and disease complications including iron overload in a beta-thalassemia mouse model (Suragani R, Blood 2014). Aims. This is an ongoing, phase 2, multicenter, open-label, dose-finding study to evaluate luspatercept in adults with transfusion-dependent (TD) or non-transfusion dependent (NTD) beta-thalassemia. Efficacy outcomes include erythroid response including Hb increase in NTD patients and reduction in RBC transfusion burden in TD patients, and reduction in liver iron concentration (LIC) by MRI in both TD and NTD patients. Methods. Inclusion criteria included age ≥ 18 yr and either TD (defined as ≥4 RBC units transfused in the 8 weeks prior to first dose, confirmed over 6 months) or NTD (defined as Results. Preliminary data (as of 10-Apr-2015) were available for 39 patients, 35 patients from dose escalation, and 4 patients from the expansion. Median age was 40 yr, ranging from 20-57 yr, and 82% had prior splenectomy. TD patients (n=14). Transfusion burden prior to treatment ranged from 4 to 12 units/12 weeks. Ten of 14 (71%) patients were treated for ≥12 weeks and were evaluable for the primary endpoint of ≥20% reduction in transfusion burden. All 10 of these patients responded with >40% reduction in transfusion burden over any 12-week period during the study. Reduction in transfusion burden correlated with reduction in LIC. Two of the 3 TD patients with baseline LIC ≥7 mg/g dw (all on iron chelation therapy) had a reduction in LIC at 16 weeks (-2.0 and -4.7 mg/g dw). NTD patients (n=25). Median baseline Hb was 8.4 g/dL (range 6.5-9.6 g/dL). Four of 8 (50%) patients in the 0.8-1.25 mg/kg dose groups achieved the primary endpoint of increase in Hb ≥1.5 g/dL sustained for ≥2 weeks, compared with 0 of 17 (0%) patients in the 0.2-0.6 mg/kg dose groups. Four of eight (50%) patients in the 0.8-1.25 mg/kg dose groups had a mean increase in Hb ≥1.0 g/dL sustained for ≥12 weeks, compared with 5 of 17 (29%) patients in the 0.2-0.6 mg/kg dose groups. Eight of 12 (67%) NTD patients with baseline LIC ≥5 mg/g dw (including 6 patients on iron chelation therapy) had a reduction of at least 1 mg/g dw in LIC at 16 weeks; reduction in LIC correlated with increase in hemoglobin. All 3 patients with chronic leg ulcers at baseline (2 NTD, 1 TD) had substantial, rapid healing, evident within 6 weeks after the first dose of luspatercept. Luspatercept was generally well tolerated, with no related serious adverse events reported to date. Adverse events were mostly mild-moderate; most frequent related adverse events (>10% patients) were bone pain, myalgia, headache and asthenia. Longer-term treatment data from the extension study for TD and NTD patients will be presented. Conclusions. Luspatercept treatment for up to 3 months was well-tolerated, increased Hb levels in NTD patients, and decreased transfusion requirement in TD patients with beta-thalassemia. Both TD and NTD patients also had decreases in LIC, and healing of leg ulcers occurred in 3 of 3 patients. These treatment effects represent a significant reduction in disease burden for patients with beta-thalassemia. Phase 3 studies of luspatercept in beta-thalassemia are planned. Disclosures Piga: Celgene Corporation: Honoraria; Acceleron Pharma: Research Funding. Zhang:Acceleron: Employment. Bellevue:Acceleron: Employment. Wilson:Acceleron: Employment. Laadem:Celgene Corporation: Employment. Sherman:Acceleron Pharma: Employment. Attie:Acceleron: Employment.