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Background: Chronically transfused homozygous sickle cell disease (HbSS) patients were shown to have higher kidney iron deposition than thalassemia major patients, not associated to total body iron and mainly caused by chronic hemolysis. Kidney iron deposition has not been explored in sickle beta-thalassemia (Sβ-thal), resulting from the inheritance of both sickle cell and beta-thalssemia genes. Aim: This multi center study aimed to study frequency, pattern, and associations of renal iron accumulation in sickle beta-thalassemia. Methods: Thirty-three Sβ-thal patients (36.49±14.72 years; 13 females) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia (E-MIOT) network were considered. Moreover, 20 healthy subjects, 14 HbSS patients and 71 thalassemia major (TM) patients were included as comparison groups. Hepatic, cardiac, pancreatic, and renal iron overload was quantified by the gradient-echo T2* technique. In each kidney T2* was measured in anterior, posterolateral, and posteromedial parenchymal regions and the global T2* value was calculated as the average of the two kidneys T2* values. Results. Global renal T2* were significantly higher in healthy subjects versus both Sβ-thal patients (49.68±10.09 ms vs 43.19±8.07 ms; P=0.013) and HbSS patients (49.68±10.09 ms vs 26.21±17.07 ms; P Sβ-thal patients showed comparable age, sex, frequency of regular transfusion, hematochemical parameters, and hepatic, cardiac and pancreatic iron load than HbSS patients, but they had a significant lower frequency of renal iron overload (global renal T2* Regularly transfused patients (16 Sβ-thal and 10 HbSS) were compared with TM patients, homogeneous for age and sex, but TM started regular transfusions significantly earlier and they were more frequently chelated. No significant difference was detected in terms of hepatic and cardiac iron levels, but TM patients had significantly lower pancreas T2* values than both the other two groups and significantly higher global renal T2* values than HbSS patients (42.87±9.43 ms vs 24.39±15.74 ms; P=0.001). In Sβ-thal patients no significant difference was detected between T2* values in left and right kidneys, and global renal T2* values were not associated to age, gender, splenectomy, and they were comparable between regularly transfused and non transfused patients. No correlation was detected between renal T2* values and serum ferritin levels or iron load in the other organs. Global renal T2* values were not associated with serum creatinine levels but showed a significant inverse correlation with serum lactate dehydrogenase (Figure 1). Conclusion. Renal iron deposition is not common in Sβ-thal patients, with a prevalence significantly lower compared to that of HbSS patients, but with a similar underlying mechanism due to the chronic hemolysis. Figure 1 Figure 1. Disclosures Pepe: Bayer S.p.A.: Other: no profit support; Chiesi Farmaceutici S.p.A: Other: no profit support. Maggio: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees.

Introduction. Pancreatic iron deposition is a common finding in thalassemia major, being detected in more than one third of patients undergoing their first T2* Magnetic Resonance Imaging scan (MRI) for this purpose. However, no longitudinal studies on pancreatic iron are available in literature. Aim: The aim of this multicenter study was to evaluate the changes in pancreatic iron overload in TM patients enrolled in the Extension-Myocardial Iron Overload in Thalassemia (E-MIOT) Network who performed a baseline and a follow-up (FU) MRI scan at 18 months. Methods. We considered 416 TM patients (37.77±10.46 years; 220 females) consecutively enrolled. Iron overload was quantified by the T2* technique. T2* measurements were performed over pancreatic head, body and tail and global value was the mean. Results. Pancreatic iron overload (global pancreas T2* A significant inverse association was detected between % change in global pancreas T2*and baseline global pancreas T2* values (R=-0.369; P Changes (%) in global pancreas T2* were not associated with baseline serum ferritin levels or MRI liver iron concentration (LIC) values but were inversely correlated with % changes in serum ferritin levels (R=-0.199; P At baseline MRI, 169 patients showed an alteration of glucidic metabolism: 32 had impaired fasting glucose, 65 impaired glucose tolerance, and 72 diabetes mellitus. These patients showed significantly higher % changes in global pancreas T2* than patients with a normal glucidic metabolism (33.06±79.48% vs 11.93±59.47%; P=0.003). Conclusions. Our data showed that it is difficult to remove the iron from the pancreas and higher improvements were detected in more heavily loaded patients, with alterations of glucidic metabolism. The reduction in pancreatic iron was paralleled by a decrease in hepatic and cardiac iron. Figure 1 Figure 1. Disclosures Pepe: Bayer S.p.A.: Other: no profit support; Chiesi Farmaceutici S.p.A: Other: no profit support. Maggio: Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Background.The T2* cardiovascular magnetic resonance (CMR) is the gold standard for the non invasive detection of myocardial iron overload (MIO). The native myocardial T1 mapping has been proposed as a complementary tool, thanks to its higher sensitivity in presence of small amounts of iron, but no data are available in literature about its clinical impact. Objective:To explore the clinical impact of T1 mapping for detecting cardiac complications in thalassemia major (TM). Methods.We considered 146 TM patients (87 females, 38.7±11.1 years) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network. Three parallel short-axis slices of the left ventricle (LV) were acquired with the Modified Look-Locker Inversion recovery (MOLLI) sequence. The native T1 values in all 16 myocardial segments were obtained and the global value was the mean. Results.Twenty-one patients had an history of cardiac complications: 11 heart failure, 8 arrhythmias (7 supraventricular and 1 ventricular), and 2 pulmonary hyperthension. Patients with cardiac complications had significantly lower global heart T1 values (879.3±121.9 ms vs 963.2±98.5 ms; P Conclusion:We found out a significant association between decreased native global heart T1 values and a history of cardiac complications, suggesting that an early detection of myocardial iron burden by native T1 can support the clinicians in modifing chelation therapy earlier. Figure Disclosures Pepe: ApoPharma Inc.:Other: no profit support;Bayer:Other: no profit support;Chiesi Farmaceutici S.p.A.:Other: no profit support and speakers' honoraria.Pistoia:Chiesi Farmaceutici S.p.A.:Other: speakers' honoraria.Meloni:Chiesi Farmaceutici S.p.A.:Other: speakers' honoraria.

Background Thalassemia Syndromes (TS) are commonly classified as transfusion-dependent-thalassemia (TDT) or non-transfusion-dependent thalassemia (NTDT) at diagnosis on the basis of requirement for lifelong regular transfusion therapy for survival. However, data from observational studies and expert opinion suggest that these categories may reflect a wide spectrum rather than a dichotomy, and may actually be interchangeable at many parts of the disease journey. Thus, an evaluation of alternate clusters to classify TS patients remains of merit. Aims The aim of this study was to cluster TS patients on the basis of possible clinical indicators of phenotype severity (IPhS) using suitable algorithms and to determine whether these are able to detect cohorts with different clinical phenotypes. Methods Representatives from thirteen international centers from seven countries agreed on 19 IPhS to be collected for a retrospective study. Data from 7910 TS patients were collected. NbClust R Packagewas performed for exploring the existence of a substructure inside the studied TS population, determining the best number of clusters. Unsupervised Random Forest (RF)clustering and the Partitioning Around Medoids (PAM)algorithms were performed to define the clusters. The most important IPhS in defining clusters were selected according to the Gini index. Kaplan-Meier (K-M) survival curves of the identified clusters, defined by the selected IPhS, were used to represent the risk of death for these clusters. Results NbClust method showed the existence of three possible clusters. The RF-PAM procedure defined three distinct clusters with a classification error rate of 4.3% (Fig 1). Moreover, the most important IPhS were patient age, mean serum ferritin level, age at diagnosis, age at first transfusion, age at first iron chelation, and number of complications. K-M curves showed statistically significant differences in survival among the three clusters (p Conclusions The observation of statistically significant differences in survival between the three newly identified clusters but not the original TDT-NTDT classification confirms that the latter classification is interchangeable, and a new triad classification system is required. These findings warrant further evaluation in prospective studies to determine specific thresholds for IPhs indicators that can aid physicians in assigning classes and tailoring care, in order to improve survival in TS patients. Disclosures Meloni: Chiesi Farmaceutici S.p.A.: Other: speakers' honoraria. Pistoia:Chiesi Farmaceutici S.p.A.: Other: speakers' honoraria. Vichinsky:Novartis: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Agios Pharmaceuticals: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; GBT: Consultancy, Research Funding.

Introduction.The presence of iron deposits results in a significant reduction in all magnetic resonance imaging (MRI) relaxation times (T1, T2 and T2*). In the clinical setting the T2* technique is the method of choice for cardiac iron quantification and it has revolutionized the management of patients with hemoglopinopathies. Purpose.To compare myocardial T2 against T2* in patients with thalassemia major (TM) for myocardial iron characterization. Methods.133 TM patients (79 females, 38.4±11.3 years) enrolled in the Extension Myocardial Iron Overload in Thalassemia (eMIOT) Network were considered. T2 and T2* images were acquired, respectively, with multi-echo fast-spin-echo and gradient-echo sequences. Global heart T2 and T2* values were obtained by averaging the values in all 16 myocardial segments. The normal T2 range was established as mean±2 standard deviations on data acquired on 80 healthy volunteers (males: 48-56 ms and females: 50-57 ms). The lower limit of normal for global heart T2*, established on the same healthy population, was 32 ms. Results.A significant correlation was detected between global heart T2 and T2* values (R=0.577; P Out of the 113 (84.9%) patients with a normal global heart T2* value, none had a decreased global heart T2 value, while 58 (51.3%) had an increased T2 value. Out of the 20 patents with a decreased global heart T2* value, only 10 (50%) had also a reduced T2 value. Conversely, 9 (45.0%) had a normal global heart T2 value and one (4.5) showed an increased T2 value. The 59 patients with increased global heart T2 value were significantly older than the remaining patients (40.8±10.5 vs 36.4±11.6 years; P=0.019) Conclusion.All patients with decreased T2 value had also a decreased T2* value and in half of the patients iron load was undetected by T2, suggesting that T2 mapping does not offer any advantage in terms of sensitivity for MIO assessment. However, more than half of TM patients had an increased T2 value, thus may be caused by the presence of myocardial inflammation and/or edema. So, T2 mapping could reveal subclinical myocardial involvement in TM patients. Figure Disclosures Pistoia: Chiesi Farmaceutici S.p.A.:Other: speakers' honoraria.Meloni:Chiesi Farmaceutici S.p.A.:Other: speakers' honoraria.

Background.Cardiovascular magnetic resonance (CMR) is the only available technique for the non-invasive quantification of MIO. The native T1 mapping has recently been proposed as an alternative to the universally adopted T2* technique, due to the higher sensitivity for detection of changes associated with mild or early iron overload. Objective.To study the association between T1 values and left ventricular (LV) function in thalassemia major (TM) and to evaluate for the first time if T1 measurements quantifying MIO are influenced by macroscopic myocardial fibrosis. Methods.146 TM patients (87 females, 38.7±11.1 years) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network underwent CMR. Native T1 values were obtained by Modified Look-Locker Inversion recovery (MOLLI) sequence in all 16 myocardial segments and the global value was the mean. LV function parameters were quantified by cine images. Late gadolinium enhancement (LGE) technique was used to detect macroscopic myocardial fibrosis. Results.No correlation was detected between global heart T1 values and LV volume indexes, LV mass index, or LV ejection fraction. Foourteen (9.6%) patients had an abnormal LV motion (13 hypokinesia and 1 dyskinesia) and they showed significantly lower global heart T1 values than patients without LV motion abnormalities (883.8±139.7 ms vs 959.0±91.3 ms; P=0.049). LGE images were acquired in 88 patients (60.3%) and macroscopic myocardial fibrosis was detected in 36 patients (40.9%). The 72.2% of patients had two or more foci of fibrosis. Patients with macroscopic myocardial fibrosis had significantly lower global heart T1 values (921.3±100.3 ms vs 974.5±72.7 ms; P=0.027) (Figure 1A). Data about the LGE was present for 1408 segments (88 patients x 16 segments) and 105 (7.5%) were positive. Segments with LGE had significantly lower T1 values than segments LGE-negative (905.6±110.6 ms vs 956.9±103.8 ms; P Conclusion.No correlation between T1 values and LV function parameters was detected, probably because the majority of the patients had normal or mild abnormal LV parameters. TM patients with macroscopic myocardial fibrosis showed significantly lower T1 values suggesting that T1 measurements for quantifying MIO are not influenced by macroscopic myocardial fibrosis and an association between myocardial iron and macroscopic fibrosis, previously detected only in pediatric TM patients. Figure Disclosures Pepe: Chiesi Farmaceutici S.p.A.:Other: no profit support and speakers' honoraria;Bayer:Other: no profit support;ApoPharma Inc.:Other: no profit support.Pistoia:Chiesi Farmaceutici S.p.A.:Other: speakers' honoraria.Meloni:Chiesi Farmaceutici S.p.A.:Other: speakers' honoraria.

Introduction. A prospective magnetic resonance imaging (MRI) study demonstrated a good control of myocardial iron overload (MIO) in terms of prevention and treatment in children with thalassemia major (TM). The aim of the present study was to evaluate if changes in MIO were related to baseline hepatic iron or changes in hepatic iron overload (HIO). Methods. We considered 68 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) project with less than 18 years at the first MRI scan and who performed a follow-up (FU) study at 18±3 months. Myocardial and hepatic iron burdens were quantified by the T2* technique. The value of 20 ms was used as conservative normal value for the global T2* value. Liver T2* values were converted into liver iron concentration (LIC) values. A LIC Results. Thirty-six patients were females and mean age at the time of the baseline MRI was 13.74±3.09 years. Baseline global heart T2* values were 29.72±11.21 ms and 16 (23.5%) patients showed significant baseline MIO. The percentage changes in global heart T2* values per month in the whole patient population were 0.66±1.70 and they resulted significantly higher in the 16 patients with significant baseline MIO versus the patients with no baseline MIO (1.99±2.53% vs 0.25±1.09% ms; P=0.002). Percentage changes in global heart T2* values per month were not influenced by initial MRI LIC values (R=0.048; P=0.695) (Figure 1A) and were comparable among the 4 groups of patients identified on the basis of baseline MRI LIC values (14 no HIO: 0.29±1.12% vs 21 mild HIO: 0.75±1.56% vs 15 moderate HIO: 0.82±2.03% vs 18 severe HIO: 0.71±2.00%; P=0.876). Percentage changes in global heart T2* values per month were not associated to final MRI LIC values (R=-0.134; P=0.277) (Figure 1B). The correlation between % changes in global heart T2* and MRI LIC values did not reach the statistical significance (R=-0.244; P=0.067) (Figure 1C). In patients with baseline MIO no correlation was found between % changes in global heart T2* values per month and initial MRI LIC values (R=-0.325; P=0.219) or % changes in MRI LIC values per month (R=-0.353; P=0.180). Conclusion. In pediatric TM patients changes in cardiac iron are not correlated to baseline MRI LIC values and changes in hepatic iron. So, our data seem not supporting the hypothesis for which it is necessary to clean the liver before removing iron from the heart. Figure 1 Disclosures Pepe: Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.

Introduction: Cardiac magnetic resonance (CMR) is the non-invasive gold standard for the quantification of biventricular functional parameters and for myocardial tissue characterization. The aim of this study was to prospectively assess the predictive value of CMR parameters for cardiovascular complications in sickle cell disease (SCD) patients. Methods: We considered 102 white SCD patients (34.38±12.67 years, 53 females) consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) network. Myocardial iron overload (MIO) was measured by the multislice multiecho T2* technique. Atrial dimensions and biventricular function parameters were quantified by cine images. Results: At baseline CMR only two patients had MIO (global heart T2* During a mean follow-up was of 63.29±24.41 months, 10 cardiac events (9.8%) were registered: 3 pulmonary hypertension, 1 pulmonary embolism, 1 peripheral vascular disease, 1 transient ischemic attack, 2 supraventricular arrhythmias, 1 heart failure, and 1 death after acute chest syndrome. CMR predictors of cardiovascular events at univariate analysis were left ventricular ejection fraction and right ventricular mass index (see Table). Both variables remained independent predictors at multivariate analysis (see Table). Conclusions: Reduced left ventricular ejection fraction and increased right ventricular mass index showed a significant prognostic value in patients with SCD. Our data seem to suggest that also CMR could be added as screening tool for identifying SCD patients at high risk for pulmonary and systemic vasculopathy and death. Table Disclosures Pepe: Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.

Background: Non-transfusion-dependent thalassemia (NTDT) is a term used to indicate patients who do not require lifelong regular transfusions for survival. Morbidity in NTDT patients is more common and serious than previously recognized. This study aimed to examine the association of age with the presence of iron overload assessed by Magnetic Resonance Imaging (MRI) and cardiovascular and endocrine complications in NTDT patients. Methods: We considered 170 patients with thalassemia intermedia never transfused o who received occasional transfusions consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) project. Iron overload was quantified by the T2* Magnetic Resonance Imaging (MRI) technique. All complications were classified according to international guidelines. Results: Six groups of patients were identified: age The youngest patient showing hepatic iron (MRI liver iron concentration-LIC>3 mg/g dw) had 9 years of age and the frequency of hepatic iron did not significantly increase with age. Only one patient showed cardiac iron (global heart T2* Diabetes appeared only in patients with more than 50 years and showed a trend toward increasing with increasing age. Hypothyroidism and osteoporosis were not present in pediatric patients and were not associated to age. Hypogonadism was not present in patients with less than 30 years and its frequency was comparable among the age groups. No patient showed hypoparathyroidism. Only patients older than 30 years showed a cardiac complication (heart failure or arrhythmias), but the rate did not significantly increase with increasing age. Conclusions: Our data in NTDT are indicative of high rate of liver iron overload at early age and extremely rare cardiac iron overload. Endocrine or cardiac complications were not present in pediatric patients but in adult patients the frequency did not increase with advancing age. Table. Table. Disclosures Pepe: Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.

Background: In non transfusion dependent thalassemia (NTDT) the lack of a clear genotype-phenotype relationship complicates the already complex and extensive scenario in clinical practice. Our aim was to detect if the presence of a β°/β° homozygous genotype is associated to increased iron overload and rate of complications. Methods: We considered 81 patients with thalassemia intermedia never transfused o who received occasional transfusions (37.7±11.4 years, 39 females) enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) project. Magnetic Resonance Imaging (MRI) was used to quantify iron overload (T2* technique), biventricular morphological and functional parameters (cine sequences), and the presence of myocardial fibrosis (late gadolinium enhancement-LGE technique). All complications were classified according to international guidelines. Results: Two groups of patients were identified: non homozygous β°/ β° genotype (N=61) and homozygous β°/ β° genotype (N=20.) No significant differences for sex and age were found between the groups. The frequency of non chelated patients was significantly lower in the homozygous β°/β° group (17.6% vs 49.1%; P=0.026) and the frequency of desferrioxamine therapy was 70.6 in the homozygous β°/β° group and 43.4 in the non homozygous β°/β° group (P=0.051). Patients with homozygous β°/β° genotype had lower mean haemoglobin levels (8.6±1.1g/dl vs 9.2±1.2 g/dl) but the difference did not reach the statistical significance (P=0.060). Serum ferritin levels, liver transaminases and MRI liver iron concentarion (LIC) values were comparable between the groups. No patient showed cardiac iron and global heart T2* values were comparable between the two groups. Left atrial area index, left ventricular (LV) end-diastolic, end-systolic and stroke volume indexes, LV mass index, right ventricular end-diastolic and end-systolic volume indexes were significantly higher in the homozygous β°/β° group (see Table). Frequencies of heart failure and arrhythmias were comparable between the groups. No patient showed diabetes or hypoparathyroidism and there was no difference between groups in terms of frequency of hypogonadism or hypothyroidism. Conversely, patients with homozygous β°/β° genotype had a significant higher frequency of osteoporosis (50.0% vs 16.7%; P=0.003). Among patients with osteoporosis, 75% were treated with DFO therapy. Conclusions: Heart remodelling related to a high cardiac output state cardiomyopathy was more pronounced in patients with homozygous β°/β° genotype. Osteoporososis was significantly more frequent in patients with homozygous β°/β° genotype, treated for more than two-thirds with DFO therapy. These data support the knowledge of different phenotypic groups in the management of NTDT patients. Table Table. Disclosures Pepe: Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.

Introduction. T2* measurement of myocardial iron overload (MIO) is presently the gold standard for monitoring and tailoring the chelation in thalassemia patients. Native T1 mapping has been proposed also for the MIO quantification because it is known that iron can reduce native T1 values. No data are available in literature comparing T1 and T2* mapping using a segmental approach including the whole left ventricle. The goal of our study was to assess the relationship between T1 and T2* values using a segmental approach. Methods. 29 patients with hemoglopinopathies (18 females, 45.39±13.49 years) enrolled in the Extension Myocardial Iron Overload in Thalassemia (eMIOT) Network were considered. Native T1 and T2* images were acquired, respectively, with the Modified Look-Locker Inversion recovery (MOLLI) and with the multi-echo gradient-echo techniques. Three parallel short-axis views (basal, medium and apical) of the left ventricle (LV) were acquired with ECG-gating. The myocardial T1 and T2* distribution was mapped into a 16-segment LV model, according to the AHA/ACC model. The lower limit of normal for each segment was established as mean±2 standard deviations on data acquired on 14 healthy volunteers. In 25 patients also post-contrastografic images were acquired. Results. T1 images showed more pronounced motion artifacts and lower contrast-to-noise-ratio, determining the exclusion of 18/464 segments. No segments were excluded by T2* mapping. So, globally, 446 segmental T1 and T2* values were considered. The mean of all segmental T2* and T1 values were, respectively, 37.83±11.30 ms and 982.72±118.24 ms. Normal T2* and T1 values were found in 374 segments (83.9%) while 29 (6.5%) segments had pathologic T2* and T1 values. For 33 segments (7.4%) (13 patients) a pathologic T1 value was detected in presence of a normal T2* value. For 10 segments (2.2%) a pathologic T2* value was detected in presence of a normal T1 value. Out of the 9 patients with pathologic T2* values in presence of normal T1, in 7 patients post-contrastografic images were acquired; in all segments with pathologic T2* value macroscopic fibrosis by late gadolinium enhancement technique and/or microscopic fibrosis by T1 mapping were found. The relation between segmental T1 and T2* values is shown in the figure. For patients with pathologic segmental T2* values there was a linear relationship between T1 and T2* values (R=0.735, P Conclusion. T2* and T1 mapping showed a good correlation in identifying iron by a segmental approach. However, we found a scatter between results. In 9 patients T1 mapping was not able to detect iron probably due to the presence of macroscopic and/or microscopic fibrosis that it is known to increase the native T1 . Conversely, in 13 patients T1 mapping seems to be more sensitive than T2* (sensitive to different iron chemistry or error measurements?). Further studies on larger population and correlation with clinical outcome are need. Figure. Figure. Disclosures Pepe: Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.

Introduction. The MIOT (Myocardial Iron Overload in Thalassemia) Network was a national Italian network constituted by thalassemia and magnetic resonance imaging (MRI) centers built in 2006. The main aim was to assure available, accessible homogeneous and standardized T2* MRI cardiac and liver iron overload assessments for a significant number of patients with emoglobinopathies. Moreover, the creation of a solid clinical-instrumental web based database allowed data exchange between centers and constituted a means of monitoring health care processes and outcomes. We describe the impact of this ten-year Network on cardiac complications in patients with thalassemia major (TM). Methods. Among the 2497 emoglobinopathies patients consecutively enrolled in the MIOT Network we considered the 1401 TM patients who performed an end-of-study MRI. Per protocol the MRI follow up was scheduled every 18±3 months. Myocardial iron overload (MIO) was quantified by the multislice multiecho T2* technique. Biventricular function was quantified by cine images. Results. At the last MRI significantly higher global heart T2* values (35.5±10.7 ms vs 29.2±12.0 ms; P In patients with significant baseline MIO (global heart T2* Based on MRI results the 75% of the patients changed the chelation therapy. At the last MRI the percentage of patients with an excellent/good compliance was significantly higher (94.7% vs 92.7%%; P=0.034). The 13.1% of the patients had a cardiac complication (heart failure, arrhythmias, pulmonary hypertension, myocardial infarction, angina, myo/pericarditis, and peripheral vascular disease) before the enrolment in the project. During the study, the frequency of cardiac complications was 7.9 %, significantly lower (P Conclusion. Over a period of 10 years, the continuous monitoring of cardiac iron levels and a tailored chelation therapy allowed a reduction of MIO in the 70% of patients and a consequent improvement of cardiac function and reduction of heart failure. So, a national networking as the MIOT project was effective in improving the care and reducing cardiac outcomes of TM patients. Figure 1 Figure 1. Disclosures Pepe: Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.

Introduction. Transfusion-dependent β-thalassemia (TDT) is the most severe clinical form of β-thalassemia and requires regular long-term red cell transfusions for survival. This study aimed to examine the association of age with the presence of iron overload assessed by Magnetic Resonance Imaging (MRI) and cardiovascular and endocrine complications in TDT patients. Methods. We considered all TDT patients enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) project at the first MRI examination. Iron concentrations were measured by T2* multiecho technique. All complications were classified according to international guidelines. Results. Three groups of patients were identified: age The number of transfusional units in the 12 months before the MRI scan resulted significantly lower in group 0 versus both group 1 (20.8±5.3 vs 34.8±10.6; P0.0001) and in group 1 versus group 2 (P=0.021). The Table shows the comparison of clinical characteristics among the 3 groups. Serum ferritin levels were significantly higher in both groups 0 and 1 when compared to group 2. Liver aminotransferases were significantly lower in group 1 than in group 2. The number of patients with MRI LIC (liver iron concentration) >3 mg/g dw was significantly higher in group 1 than in group 2 and the number of patients with global heart T2* Among the endocrinopathies, hypogonadism, hypothyroidism and osteoporosis were significantly less frequent in groups 0 and 1 than in group 2 while diabetes was significantly less frequent only in group 1 when compared to group 2. Frequency of heart failure was comparable among the groups while the frequency of arrhythmias was significantly lower in group 1 than in group 2. The types of chelation regimens were significantly different among groups ( Conclusions. Younger patients had more hepatic iron, despite the significant lower transfusional burden. Cardiac iron overload occurs early in TDT patients but it is more frequent in older patients. Endocrinopathies (excluding diabetes) and cardiac complications become clinically evident during the second decade and are time-dependent processes. Our data suggest the need for an effective strategy to prevent iron overload since early childhood, in order to reduce its toxic effect and prevent the development of long-term complications. Figure. Figure. Disclosures Pepe: Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.

Introduction. Beta thalassemia major (β-TM) displays a great deal of genotypic heterogeneity, not fully investigated in terms of cause-effect. This prospective and multicentre study aimed to detect if different genotypic groups could predict the development of cardiovascular magnetic resonance (CMR) abnormalities and cardiac complications (CC). Methods. We considered 708 β-TM patients (373 females, 30.05±9.47 years), consecutively enrolled in Myocardial Iron Overload in Thalassemia (MIOT) network. Data were collected from birth to the first CMR imaging scan. Myocardial iron overload was assessed by the multislice multiecho T2* technique. Biventricular function parameters were quantified by cine images. Late gadolinium enhancement (LGE) images were acquired to detect myocardial fibrosis. Results. On the basis of the type of gene mutation, three groups of patients were identified: homozygotes β+ (N=158), compound heterozygotes β+ / β° (N=298) and homozygotes β° (N=252). Table 1 shows the effect of genotype group on the development of different cardiac outcomes. Compared to the milder genotype group homozygotes β+, the other two groups showed a significantly higher risk of myocardial iron overload (MIO) and left ventricular dysfunction. We recorded 90 (13.0 %) cardiac events: 46 heart failures (HF), 38 arrhythmias (33 supraventricular, 3 ventricular and 2 hypoinetic) and 6 pulmonary hypertensions (PH). No prospective association was detected between genotype group and HF and PH. The homozygous β° group showed a significantly higher risk of arrhythmias than the homozygous β+ group and at the limit of significance than the compound heterozygotes. Globally, homozygotes β° showed a significantly higher risk of CC than homozygotes β+. Conclusion. Different genotypic groups predict the development of MIO, left ventricular dysfunction, arrhythmias and CC in β-TM patients. These data support the knowledge of the different genotypic groups in the clinical management of β-TM patients. Table Table. Disclosures Pepe: Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.

Introduction. The gradient echo multiecho T2* MRI technique is the most robust method for the non invasive, sensitive, and fast quantification of organ-specific iron overload. A crucial aspect is the transferability of the T2* technique among different MRI scanners, in order to expand the availability of high-quality monitoring of iron accumulation to a large population. The intra- and inter-operator reproducibility, inter-study reproducibility, and inter-scanner reproducibility of the T2* MRI method for measuring iron concentrations in the heart and liver have already been demonstrated. However, the transferability of the MRI multislice multiecho T2* technique for pancreatic iron overload assessment has not been evaluated. Thus, the aim of our study was to assess the transferability of this approach among ten MRI sites. Methods. All subjects underwent MRI using conventional clinical 1.5T scanners of three main vendors. Fifty healthy subjects, five for each site, including the reference centre, were scanned. Five patients with thalassemia were scanned locally at each site and were rescanned at the reference site in Pisa within 1 month. T2* image analysis was performed using custom-written, previously validated software (HIPPO MIOT®). T2* values over pancreatic head, body and tail were calculated and the global pancreatic T2* value was obtained as the mean. The lowest threshold of normal T2* value was 26 ms6. Results. On healthy subjects the global pancreas T2* values ranged from 28.93 to 48.89 ms (mean 37.88 ms, SD 5.08 ms). No significant difference was detected among the sites (P=0.334). Table 1 shows the global pancreas T2* values measured at the different MRI sites. The global pancreas T2* values ranged from 2.08 to 38.39 ms. There was not a significant difference between the T2* values measured in the MRI sites and the correspondent values observed in Pisa (12.02±10.20 ms vs 11.98±10.47 ms; P=0.808). All patients categorized as having pancreatic iron overload in the MRI sites, fell in the same category after the MRI executed in Pisa. There was a strong correlation between the global pancreas T2* values calculated from images obtained in Pisa and at the other MRI sites (R=0.978, P Figure 1 shows the global pancreas T2* values calculated from images obtained at the 9 MRI sites as a function of global pancreas T2* calculated from images obtained in Pisa. The line of best fit had a slope of 0.965 ± 0.021 and an intercept of 0.459 ± 0.328 ms. The R-squared value for the fit was 0.981. Neither constant bias (intercept did not significantly differs from zero) nor proportional bias (angular coefficient did not significantly differ from 1) affected the measurements. CoVs for all MRI sites are provided in Table 2; they ranged from 4.22 to 9.77%. The CoV for all the T2* values independently from the sites was 8.55%. The ICC considering all the T2* values, independently from the sites, was 0.995. The ICC for each MRI site is provided in Table 2 and it was always excellent. The comparison between Pisa and the other MRI sites by Bland-Altman analysis showed a mean absolute difference of -0.04 ± 1.47 ms for the global pancreas T2* values (Figure 2). No bias was present and no greater differences for higher T2* values were detected. The mean absolute difference in patients with pancreatic iron (N=39) was -0.15 ± 1.38 ms. Conclusion. The gradient-echo T2* MRI technique is an accurate and reproducible means for the calculation of pancreatic iron and may be transferred between MRI scanners in different centers from different manufacturers. Figure. Figure. Disclosures Pepe: Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.

Introduction. Thalassemia Syndromes (TS) are currently categorized as transfusion dependent (TDT, primarily Thalassemia Major patients) and non transfusion dependent (NTDT, primarily Thalassemia Intermedia patients). TDT includes patients who need regular transfusions for survival with at least ≥7 ml/kg/month of packed red blood cells. NTDT is a term used to label patients who do not require lifelong regular transfusions for survival, although they may require occasional or even frequent transfusions in certain clinical settings and usually for defined periods of time. Therefore, the current TS classification suggests two defined classes of disease severity, TDT and NTDT, with different prognosis. However, recent survival studies in Western and Eastern countries showed that life expectancy of TDT is today quite similar to that of NTDT (Vitrano et al. Br J Haematol. 2017; Rajaeefard et al. Epidemiol Health 2015). The main aim of this study was to revisit the dichotomous classification of TS towards a classification including a "continuum" of the same disease divided in multiple stages according to the severity of phenotypes. Methods. This was a retrospective study on patients with TDT and NTDT, born after February 13, 1965 (data of approval of Deferoxamine chelation treatment), and attending 9 Italian centres. Our Ethical Committee approved the protocol on May 25, 2017. Focusing on clinical severity indicators, a cluster analysis was performed to explore if the current TS classification fits with two classes of risk, regardless if the patients had TDT or NTDT. The following indicators of clinical severity were selected: 1) age at first transfusion, years; 2) age at starting chelation, years; 3) transfusion therapy (yes/no); 4) Mean serum ferritin levels, ng/ml; 5) number of complications. Cluster analysis was applied at these indicators with the task of grouping a set of statistical units in such a way that units in the same group (cluster) will be more similar to each other than to those in other clusters. If current classification fits with clinical severity of TS, only two classes of risk matching TDT and NTDT should be identified. Results. Overall 1547 patients, 1332 with TDT (mean age 35.6±0.2 years) and 215 with NTDT(mean age 38.4±0.5years), were included in the study. Mean age at first transfusion was 1.5±0.04 years and 8.4±9.4 years in TDT and NTDT, respectively.Mean age at starting chelation was 4.6±0.1 years in TDT and 13.6±11.4 years in NTDT. Splenectomy was more common in NTDT (80.2%) than TDT ( 51.9%). Diabetes, heart failure and hypogonadism were most frequent in TDT, while cirrhosis was equally distributed. Figure 1 shows results from cluster analysis suggesting that it was not possible to classify TS only into two separate groups. The two obtained clusters intersect an area were patients with TDT and NTDT had very similar clinical features. Patients could not be divided by their clinical profiles between TDT or NTDT distinct groups (Fig. 1). Table 1 shows some TDT and NTDT patients allocated in two different clusters but with very similar clinical profiles. Conclusions. Cluster analysis suggests that the classes of risk of TDT and NTDT may not fit with current classification of TS. Indeed, some patients are detected in the same area of the clusters, independently from onset of diagnosis. This could be due to the presence of a "continuum" phenotype from NTDT to TDT. However, an effect of conventional treatment in improving phenotype of patients with TDT could be not excluded. Therefore, to validate this hypothesis, these data have to be confirmed in a larger population, encompassing different intensity of conventional treatment. In conclusion, although these results call for a potential revision of the clinical classification of thalassemia based on strict categories of severity towards a classification including a "continuum" of the same disease divided into one that manifests in categories (Classes of Risk), this hypothesis must be validated with larger setting of patients and discussed inside of International Working Group of expert opinion leaders on this field. Disclosures Pepe: Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc.