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A prognostic scoring system that can differentiate β-thalassemia patients based on mortality risk is lacking. We analysed data from 3145 β-thalassemia patients followed through a retrospective cohort design for the outcome of death. An a priori list of prognostic variables was collected. β Coefficients from a multivariate cox regression model were used from a development dataset (n = 2516) to construct a formula for a Thalassemia International Prognostic Scoring System (TIPSS) which was subsequently applied to a validation dataset (n = 629). The median duration of observation was 10.0 years. The TIPSS score formula was constructed as exp (1.4 × heart disease + 0.9 × liver disease + 0.9 × diabetes + 0.9 × sepsis + 0.6 × alanine aminotransferase ≥42 IU/L + 0.6 × hemoglobin ≤9 g/dL + 0.4 × serum ferritin ≥1850 ng/mL). TIPSS score thresholds of greatest differentiation were assigned as2.0 (low-risk), 2.0 to5.0 (intermediate-risk), and ≥5.0 (high-risk). The TIPSS score was a good predictor for the outcome of death in the validation dataset (AUC: 0.722, 95%CI: 0.641-0.804) and survival was significantly different between patients in the three risk categories (P 0.001). Compared to low-risk patients, the hazard ratio for death was 2.778 (95%CI: 1.335-5.780) in patients with intermediate-risk and 6.431 (95%CI: 3.151-13.128) in patients with high-risk. This study provides a novel tool to support mortality risk categorization for patients with β-thalassemia that could help management and research decisions.

The thalassaemia syndromes (TS) show different phenotype severity. Developing a reliable, practical and global tool to determine disease severity and tailor treatment would be of great value. Overall, 7910 patients were analysed with the aim of constructing a complication risk score (CoRS) to evaluate the probability of developing one or more complications. Nine independent variables were included in the investigation as predictors. Logistic regression models were used for Group A [transfusion-dependent thalassaemia (TDT)], Group B [transfused non-TDT (NTDT)] and Group C (non-transfused NTDT). Statistically significant predictors included age (years), haemoglobin levels, hepatic transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase] and left-ventricular ejection fraction (LVEF) for Group A; age (years), age at first chelation (months), ALT and LVEF for Group B; and age (years), mean serum ferritin (SF) levels and LVEF for Group C. The area under the receiver operating characteristic curve was 84·5%, 82·1% and 80·0% for Groups A, Group B and Group C respectively, suggesting the models had good discrimination. Finally, the CoRS for each group was categorised into four risk classes (low, intermediate, high, and very high) using the centiles of its distribution. In conclusion, we have developed a CoRS for TS that can assist physicians in prospectively tailoring patients’ treatment.

In β-thalassaemia, the severity of inherited β-globin gene mutations determines the severity of the clinical phenotype at presentation and subsequent transfusion requirements. However, data on associated long-term outcomes remain limited. We analysed data from 2109 β-thalassaemia patients with available genotypes in a global database. Genotype severity was grouped as β0 /β0 , β0 /β+ , β+ /β+ , β0 /β++ , β+ /β++ , and β++ /β++ . Patients were followed from birth until death or loss to follow-up. The median follow-up time was 34·1 years. Mortality and multiple morbidity outcomes were analyzed through five different stratification models of genotype severity groups. Interestingly, β0 and β+ mutations showed similar risk profiles. Upon adjustment for demographics and receipt of conventional therapy, patients with β0 /β0 , β0 /β+ , or β+ /β+ had a 2·104-increased risk of death [95% confidence interval (CI): 1·176-3·763, P = 0·011] and 2·956-increased odds of multiple morbidity (95% CI: 2·310-3·784, P < 0·001) compared to patients in lower genotype severity groups. Cumulative survival estimates by age 65 years were 36·8% for this subgroup compared with 90·2% for patients in lower genotype severity groups (P < 0·001). Our study identified mortality and morbidity risk estimates across various genotype severity groups in patients with β-thalassaemia and suggests inclusion of both β+ and β0 mutations in strata of greatest severity.

Background In patients with non-transfusion-dependent beta-thalassaemia, haemoglobin concentrations lower than 10 g/dL are associated with a higher risk of morbidity, mortality, and impaired quality of life. No drugs are specifically approved for anaemia management in patients with non-transfusion-dependent beta-thalassaemia, other than transfusion therapy administered infrequently in accordance with patients' needs. We assessed the efficacy and safety of luspatercept versus placebo in patients with non-transfusion-dependent beta-thalassaemia.Methods We did a phase 2, randomised, double-blind, multicentre, placebo-controlled trial in 12 centres in six countries (Thailand [n=1], Lebanon [n=1], Greece [n=2], Italy [n=5], the UK [n=1], and the USA [n=2]). Eligible patients were aged 18 years or older, had confirmed diagnosis of beta-thalassaemia or haemoglobin E/beta-thalassaemia (concomitant a-globin deletion, mutation, or duplication were allowed), and a baseline haemoglobin concentration of 10.0 g/dL or lower. All patients were non-transfusion-dependent. Patients were randomly assigned (2:1) to luspatercept or placebo using an interactive response technology system and stratified by baseline haemoglobin concentration (>= 8.5 g/dL vs = 3 vs

Hydroxyurea (HU) has been widely used in clinical practice to manage patients with non-transfusion dependent thalassemia (NTDT). Few data are available about the effects of its administration in Italian patients. We assessed hematological and non-hematological outcomes following short- and long-term exposure to HU.We considered 71 NTDT patients (30 females) enrolled in the Myocardial Iron Overload in Thalassemia Network and treated for12 months with HU.The mean duration of HU treatment was 8.23±5.79 years, starting at a mean age of 37.02±12.06 years. A significant increase in hemoglobin and mean corpuscular volume values and a down-regulation of all erythropoietic and/or hemolysis indices were detected after at least 12 months of treatment. In 28 patients the hemoglobin increase was ≥1.0 g/dl, associated with a higher HU dose. The hematological response dropped in long-term treatment. A favorable impact of HU treatment in limiting the progression of several complications typical of NTDT syndrome was observed.Our findings seemed to suggest that in several NTDT patients HU could be still a valid option to limit the advance in overall disease clinical burden without carrying significant adverse events and increase in mortality.

In this work, we aimed to establish subgroups of clinical severity in a global cohort of β-thalassemia through unsupervised random forest (RF) clustering. We used a large global dataset of 7910 β-thalassemia patients and evaluated 19 indicators of phenotype severity (IPhS) to determine their contribution and relatedness in grouping β-thalassemia patients into clusters using RF analysis. RF clustering suggested that three clusters with minimal overlapping exist (classification error rate: 4.3%), and six important IPhS were identified: the current age of the patient, the mean serum ferritin level, the age at diagnosis, the age at first transfusion, the age at first iron chelation, and the number of complications. Cluster 3 represented patients with early initiation of transfusion and iron chelation, considerable iron overload, and early mortality from heart failure. Patients in Cluster 2 had lower serum ferritin levels, although they had a higher number of complications manifesting overtime. Patients in Cluster 1 represented a subgroup with delayed or absent transfusion and iron chelation, but with a high morbidity rate. Hepatic disease and cancer were dominant causes of death in patients in Cluster 1 and 2. Our findings established that patients with β-thalassemia can be clustered into three groups based on six parameters of phenotype severity.

Although the possibility of asymptomatic course for COVID‐19 infection in splenectomized thalassemia beta major patients is present, screening them for COVID‐19 is important as the progression is still not clear.

A retrospective magnetic resonance imaging (MRI) study on a large cohort of children with thalassemia major (TM) showed cardiac involvement by early childhood; 21% of children presented with abnormal cardiac T2* and 16% with cardiac fibrosis. Moreover, moderate and/or severe liver iron overload (IO

In this cross-sectional study we assessed the vascular alterations in retinal and choriocapillaris perfusion in patients affected by β-thalassemia, by means of optical coherence tomography angiography (OCTA). A total of 124 eyes of 62 patients (mean age 44.74 ± 5.79 years old) affected by β-thalassemia (transfusion dependent thalassemia (TDT), non-transfusion dependent thalassemia (NTDT) and minor) were compared to 40 eyes of twenty healthy subjects. We evaluated the vessel density (VD) in superficial capillary plexus, deep capillary plexus, radial peripapillary capillary, choriocapillaris and the foveal avascular zone area. The TDT group showed a statistically significant reduction in retinal and choriocapillaris VD respect to controls and the other groups (p &lt, 0.05). No statistically significant difference was found in OCTA parameters between β-thalassemia minor and controls. The NTDT group showed a significant reduction in VD in deep capillary plexus respect to controls and β-thalassemia minor. Significant negative correlations were shown in TDT group between foveal avascular zone and hemoglobin (r = −0.437, p = 0.044) and between ferritin levels and VD of choriocapillaris (r = −0.431, p = 0.038). The OCTA parameters provided a deeper understanding on retinal and choriocapillaris vascular impairment affected by tissue hypoxia levels and the oxidative stress in different clinical phenotypes of the β-thalassemia.

Aims A tailored chelation therapy guided by magnetic resonance imaging (MRI) is a strategy to improve the prognosis in iron-loaded patients, in many cases still hampered by limited MRI availability. In order to address this issue, the Myocardial Iron Overload in Thalassemia (MIOT) network was established in Italy and we aimed to describe the impact of 10-year activity of this network on cardiac burden in thalassemia major (TM). Methods and results Within the MIOT network, 1746 TM patients (911 females; mean age 31.2 ± 9.1 years) were consecutively enrolled and prospectively followed by 70 thalassemia and 10 MRI centres. Patients were scanned using a multiparametric approach for assessing myocardial iron overload (MIO), biventricular function, and myocardial fibrosis. At the last MRI scan, a significant increase in global heart T2* values and a significantly higher frequency of patients with no MIO (all segmental T2* ≥20 ms) were detected, with a concordant improvement in biventricular function, particularly in patients with baseline global heart T2* Conclusion Over 10 years, continuous monitoring of cardiac iron and a tailored chelation therapy allowed MIO reduction, with consequent improvement of cardiac function and reduction of cardiac complications and mortality from MIO-related HF. A national networking for rare diseases therefore proved effective in improving the care and reducing cardiac outcomes of TM patients.

Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox.DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (100 mg/kg per day) or deferasirox (40 mg/kg per day; deferasirox is not registered for use in children aged2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512.435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had β-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group.In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group.EU Seventh Framework Programme.

BACKGROUND: The causes and effects of genotypic heterogeneity in beta-thalassemia major (β-TM) have not been fully investigated. The aim of this multicentre study was to determine whether different genotype groups could predict the development of cardiovascular magnetic resonance abnormalities and cardiac complications. MATERIALS AND METHODS: We considered 708 β-TM patients (373 females, age 30.05±9.47 years) consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) network. Data were collected from birth to the first cardiac magnetic resonance scan. Myocardial iron overload was assessed using a T2* technique. Biventricular function was quantified by cine images. Macroscopic myocardial fibrosis was evaluated by a late gadolinium enhancement technique. RESULTS: Three groups of patients were identified: β(+) homozygotes (n=158), β(+)/β° heterozygotes (n=298) and β° homozygotes (n=252). Compared to β(+) homozygotes, the other two groups showed a significantly higher risk of myocardial iron overload and left ventricular dysfunction. We recorded 90 (13.0%) cardiac events: 46 episodes of heart failures, 38 arrhythmias (33 supraventricular, 3 ventricular and 2 hypokinetic) and 6 cases of pulmonary hypertensions. β° homozygotes showed a significantly higher risk than β(+) homozygotes of arrhythmias and cardiac complications considered globally. DISCUSSION: Different genotype groups predicted the development of myocardial iron overload, left ventricular dysfunction, arrhythmias and cardiac complications in β-TM patients. These data support the importance of genotype knowledge in the management of β-TM patients.

The phenotype/genotype relationship of patients with transfusion-dependent thalassaemia (TDT) is particularly complex and variable, thus generating different levels of severity and of annual transfusion volume (ATV). In this study, we explored the role and the contribution of several factors potentially involved in determining mean ATV in a cohort of TDT patients which have been followed since long time. We collected data on one-hundred and twenty-seven patients with transfusion-dependent β-thalassaemia followed at Rare Blood Cell Disease Unit, AORN Cardarelli Hospital. Age at first transfusion, genotype, spleen status (splenectomy or not), and mean soluble transferrin receptor (sTfR) were the parameters included in the analysis. At stepwise regression analysis which included all the parameters, only splenectomy and mean sTfR significantly predicted the mean ATV (F = 70.94, P

Introduction: Renal dysfunction is a frequent complication in patients suffering from β-thalassemia major (β-TM). The aim of this study was to analyze the renal function and urine metabolomic profile of β-TM patients undergoing transfusions and deferasirox (DFX) therapy, in order to better characterize and shed light on the pathogenesis of renal disease in this setting. Methods and Subjects: 40 patients affected by β-TM treated with DFX and 35 age- and gender-matched healthy controls were enrolled in the study. Renal function was assessed. Glomerular filtration rate (GFR) was estimated with CKD-EPI and Schwartz formula for adults and children, respectively. Renal tubular function and maximal urine concentration ability were tested. Urine specimens were analyzed by nuclear magnetic resonance spectroscopy to identify the urinary metabolite profiles. Results: The study of renal function in β-TM patients revealed normal estimated (e)GFR mean values and the albumin-to-creatinine ratio was Discussion: The major finding of this work is that β-TM patients and controls exhibit different concentrations of some metabolites in the urine. Early recognition of urinary abnormalities may be useful to detect and prevent kidney damage.

This study analysed the impact of liver steatosis (LS) on the parameters of iron overload in 110 patients with non-transfusion dependent thalassaemia (NTDT). LS was diagnosed by ultrasound. Liver iron concentration (LIC) measurements were available for 64 patients who underwent a magnetic resonance imaging (MRI) scan. LS was frequent (35·5%) and was significantly more prevalent in males than in females (49·0% vs. 24·6%, P = 0·008). Patients with LS had significant higher levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALT/AST ratio and ferritin than those without, but LIC values were comparable. An ALT/AST ratio0·89 predicted the presence of LS with a sensitivity of 0·872 and a specificity of 0·901 (P 0·0001). Ferritin levels correlated with LIC values (R = 0·558, P 0·0001) but the correlation was stronger in patients without LS (R = 0·656, P 0·0001) than in patients with LS (R = 0·426, P = 0·05). LS is a frequent issue in NTDT patients and should be suspected in the presence of an ALT/AST ratio0·89. Recently, serum ferritin thresholds that predict clinically relevant LIC for guiding iron chelation therapy when MRI is unavailable have been determined. Our data show that LS may cause increase in ferritin levels and may be responsible for anticipating/exceeding chelation treatment in NTDT patients in the absence of LIC evaluation.

Non-transfusion-dependent thalassemia includes a variety of phenotypes and genotypes that rarely require regular transfusions. However, these patients can experience a wide range of complications. The objective of this retrospective study was to verify whether there is a significant difference in non-transfusion-dependent thalassemia-related complications and treatment among males and females.We performed a re-analysis of samples evaluated in a previously published cross-sectional study, regarding 96 non-transfusion-dependent thalassemia patients followed at the 'UOSD Malattie Rare del Globulo Rosso' Centre of the Cardarelli Hospital in Naples, Italy.We found that females were more anemic than males, but there was no significant difference in prevalence of common complications among genders, except for hypogonadism. Furthermore, the transitory regular transfusions regimen in women who had been pregnant does not seem to have a significant impact on overall prognosis.In non-transfusion-dependent thalassemia patients, the lower levels of hemoglobin found in females do not seem to indicate a higher prevalence of complications.This data should be considered in studies with experimental treatments aiming to correct anemia in patients with non-transfusion-dependent thalassemia. It should probably also be taken into account in order to set up different transfusion regimens among genders in transfusion-dependent patients.

In adult thalassemia major (TM) patients, a number of occult and emerging endocrine complications, such as: central hypothyroidism (CH), thyroid cancer, latent hypocortisolism, and growth hormone deficiency (GHD) have emerged and been reported. As the early detection of these complications is essential for appropriate treatment and follow-up, the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) promoted a survey on these complications in adult TM patients, among physicians (pediatricians, hematologists and endocrinologists) caring for TM patients in different countries. The data reported by 15 countries are presented. The commonest endocrine complications registered in 3.114 TM adults are CH and GHD (4.6 % and 3.0 %, respectively), followed by latent hypocortisolism (1.2%). In 13 patients (0.41%) a cytological papillary or follicular thyroid carcinoma was diagnosed in 11 and 2 patients, respectively, and a lobectomy or thyroidectomy was carried out. Of 202 TM patients below the age of 18 years, the reported endocrine complications were: GHD in 4.5%, latent hypocortisolism in 4.4% and central hypothyrodisim in 0.5%. Transition phase was an area of interest for many clinicians, especially as patients with complex chronic health conditions are responding to new treatments extending their lifespan beyond imagination.. In conclusion, our survey provides a better understanding of physicians’ current clinical practices and beliefs in the detection, prevention and treatment of some endocrine complications prevailing in adult TM patients. Regular surveillance, early diagnosis, treatment and follow-up in a multi-disciplinary specialized setting are recommended. (www.actabiomedica.it)

Objectives The liver remains the primary site of iron storage, with liver iron concentration (LIC) being a strong surrogate of total body iron. MRI-R2 can accurately measure LIC. The LICNET (Liver Iron Cutino Network) was established to diagnostics of liver iron overload by MRI-R2 subjects with hemochromatosis in hematological disorders. The aims of the study were to look at variation in LIC measurements during time across different chelation regimens. Methods This was a cross-sectional study of 130 patients attending 9 Italian centers participating in the LICNET. LIC comparisons over time (T0 and T1 ) were made using t test and/or Wilcoxon test. Results LIC significantly decreased from MRI1 to MRI2 although at high variance (median change -0.8 mg Fe/g dw, range: -29.0 to 33.0; P = .011) and 7.7% of patients shifted from LIC values of high risk (>15 mg Fe/g dw) to an intermediate-risk category (7-15 mg Fe/g dw). Median change in LIC and correlation with serum ferritin levels (SF), during different chelation regimens, is reported. Conclusions These findings suggest as longitudinal variation in the LIC is possible, across all chelation regimens. It confirms as SF levels not always can be used for estimating changes in LIC.

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.

Objectives: Despite the correct application of blood transfusions and chelation treatments, beta thalassemia patients have many complications. Systematic population analyses on types and frequency of these complications are very few. The aim of this study is to characterize the complications, their risk factors and their clinical and economic impact. Methods: Complications at baseline and events occurring during one observational year were analyzed in 272 patients aged >12 years. Risk factors were analyzed through chi-squared and unpaired t tests. Logistic regression was applied to perform the risk factors multivariate analysis. Results: A total of 554 complications (1–6 per patient) affected 82.3% of patients. Cardiac complications were less represented than expected. Musculoskeletal diseases were the most represented complications followed by hepatic, sexual and endocrine diseases. Splenectomized patients, born before 1970 and aged >40 years, starting iron chelation therapy when aged >4 years or after receiving more than 20 blood transfusions, presented a significantly higher number of complications. A total of 885 adverse events requiring 34125 additional medical services occurred in 1 year. Of these, 34.9% were related to treatments and 65.1% to other causes. Event numbers, additional medical interventions and cost increased progressively in patients affected by one or more complication compared to patients with no complications. Conclusions: The pattern of complications changes according to birth cohort and differentiates older from younger patients. The burden of the disease and its costs increase after the onset of the first complication, therefore prevention of complications is fundamental in these patients.

AIMS: Despite long clinical experience with deferiprone, there is limited information on its pharmacokinetics in children

The management of iron overload in thalassemia has changed dramatically since the implementation of magnetic resonance imaging, which allows detection of preclinical iron overload and prevention of clinical complications. This study evaluated the effect of deferasirox (DFX), the newest once-daily oral chelator, on cardiac function, iron overload and cardiovascular events over a longer follow up in a "real world" setting. Longitudinal changes in cardiac magnetic resonance T2*, cardiac function parameters and cardiovascular clinical events were assessed in a cohort of 98 TM patients exposed to DFX for a mean of 6.9 years (range 1.8-11.6 years). No cardiac death or incident heart failure occurred. Cardiac T2* significantly increased (+2.6 ± 11.9 msec; P = 0.035) in the whole population, with a significantly greater increase (+11.6 ± 15.5 msec, P = 0.019) in patients with cardiac iron overload (T2*20 ms). A significant improvement in left-ventricular ejection fraction (LVEF) (from 50.6 ± 6 to 60.2 ± 5; P = 0.001) was observed in 11 (84.6%) out of 13 patients who normalized cardiac function (LVEF56%). Arrhythmias were the most frequent cardiac adverse event noted but none led to DFX discontinuation. Our data indicate that DFX is effective in maintaining cardiac iron level in the normal range and in improving cardiac iron overload. No heart failure or cardiac death was reported over this longer observation up to 12 years. For the first time, a DFX-induced improvement in LVEF was observed in a subgroup of patients with abnormal cardiac function at baseline, a preliminary observation which deserves further evaluation.

Background: Classification of phenotype severity in patients with beta-thalassaemia has so far relied mainly on expert opinion using parameters of genotype, clinical features at diagnosis, and transfusion requirement. The aim of this study was to use a large dataset of patients with beta-thalassaemia and evaluate a classification system based on onset variables agreed on by an international expert group, including age at diagnosis, at first transfusion, and at first iron chelation. Methods: A retrospective dataset of 7910 patients with homozygous or compound heterozygous beta-thalassaemia was used and subjected to cluster and classification analysis starting with the onset variables. Results: Cluster analysis suggested that three clusters with minimal overlapping exist. Three phenotype severity classes (mild, moderate, severe) were accordingly assigned which showed statistically significant descending variation of age at diagnosis and start of transfusion and iron chelation. The estimated classification error rate was only 3.07% with an accuracy of 96.93%. It was evident that severe patients had higher blood requirement and iron overload levels and showed a younger age for mortality especially from heart disease. Although mild and moderate patients showed the opposite in gradual severity, they still showed evidence of high morbidity rate for complications that require longer time to manifest (eg liver damage and hepatocellular carcinoma). Conclusion: Age of diagnosis and start of transfusion and iron chelation distinguish three classes of phenotype severity in beta-thalassaemia that carry unique clinical profiles. Further prospective studies are recommended to validate these findings. Funding Statement: The authors state: "None" Declaration of Interests: The authors state: " None to disclose." Ethics Approval Statement: An International Health Repository (IHR) protocol, approved on May 25th, 2017 by the Italian Ethical Committee (EudraCT and Sponsor's Protocol Code Numbers were 2017-004457-17 and 143AOR2017) was established to allow collection of relevant data.

β-thalassemia is a hereditary disorder with limited approved treatment options; patients experience anemia and its complications, including iron overload. The study aim was to determine whether luspatercept could improve anemia and disease complications in patients with β-thalassemia. This open-label, nonrandomized, uncontrolled study consisted of a 24-week dose-finding and expansion stage (initial stage) and a 5-year extension stage, currently ongoing. Sixty-four patients were enrolled; 33 were non–transfusion dependent (mean hemoglobin

Background Real-life data on the use of R2 MRI for the assessment of liver iron concentration (LIC) remain limited. Methods We conducted a cross-sectional analysis on 363 patients (mean age 35.6 yr, 44.1% men) with hemoglobinopathies (204 β-thalassemia major [TM], 102 β-thalassemia intermedia [TI], and 57 sickle cell disease [SCD]) that were evaluated with R2 MRI as part of LICNET, an MRI network of 13 Italian treatment centers. Results The mean LIC was 7.8 mg/g (median: 4.0), with high LIC (>7 mg/g) noted in both transfused (TM, TI 37%; SCD 38%) and non-transfused (TI 20%) patients. Ferritin levels correlated with LIC in both transfused (TM, TI, SCD) and non-transfused (TI) patients (P < 0.001), although lower values predicted high LIC in non-transfused patients (1900 vs. 650 ng/mL in TM vs. non-transfused TI). A correlation between LIC and ALT levels was only noted in HCV-negative patients (rs = 0.316, P < 0.001). The proportion of patients with high LIC was significantly different between iron chelators used (P = 0.023), with the lowest proportion in deferasirox (30%) and highest in deferiprone (53%)-treated patients. Conclusions High LIC values persist in subgroups of patients with hemoglobinopathy, warranting closer monitoring and management optimization, even for non-transfused patients with relatively low ferritin levels.

Introduction Thalassemia Syndromes (TS) are a group of inherited haemoglobin disorders characterized by different phenotype severity falling among heterozygote state, no transfusion dependent thalassemia (NTDT) and transfusion dependent Thalassemia (TDT) (Graffeo et al, 2018; Taher & Saliba, 2017). Several factors, independently by genotype and globin chain unbalance, modulate the severity of ineffective erythropoiesis (Rivella et al, 2015). Considering the complexity of this pathophysiology, one tool to evaluate patients on an individual basis is needed. The aim of this study was to develop a severity scoring system with a view to initiate timely interventions that would prevent any further complications. Methods An International Health Repository (IHR) protocol was approved on May 25th, 2017 by the Italian Ethical Committee (EudraCT Code Numbers 2017-004457-17 and 143AOR2017). Subsequently, an International Working Group (IWG) on Thalassemia was formed and it met in Palermo, Italy, on September 15th and 16th, 2017. Indicators of phenotype severity thought to be most pertinent in defining disease severity were shared among the IWG based on their expertise as well as on expert opinion reported on literature. These data were collected and stored on IHR platform (www.sanitasicilia.eu/IWG ). In order to define the prognostic score (PS) a retrospective multicenter case-control study was carried ahead. Overall, clinical findings of 7910 patients who attended the IWG centres from 1976 to 2018 were collected (Tab. 1). The study was based on 5657 cases that developed complications and 2253 controls that didn't develop any complications. The term "patient" was used both for cases and for controls. The variables used for the scoring system development were reported in Table 2. The PS was built using a Conditional Logistic Regression Model (CLRM) (DW. Hosmer, Jr., 2013). The full data-set was split into two data-set containing Group A and Group B patients. Group A included transfused TDT and NTDT patients, while Group B included only no transfused NTDT patients. This was necessary because of the variable "age at first transfusion" was absent in no transfused patients. The two PS will refer as Score A and Score B, respectively. The Stata 12 (StataCorp, College Station, TX, USA) was used for all analyses. Results Overall, the analysis was performed on 5657 cases (2812 Females, age at follow up 34.7±12.9) with a mortality of 8.5% and 2253 controls (1136 Females, age at follow up 22.1±12.8) with a mortality of 1.9%. Table 3 shows complications and deaths in the full data set. Moreover, it even suggests, as single patient may have more than one complication and that the cardiac complications followed by the cancer and infection were the most common. Table 4 shows the statistically significant variables for the calculation of the score. The age of the patient and at first diagnosis, the mean Hb, AST, ALT and the Left Ventricular Ejection Fraction (LVEF) were the statistically significant variables at CLRM analysis, for the Group A. The formula for the Score A=1.1x(Age)+0.9x(Age at first diagnosis)+1.3x(Hb mean)+1.006x(AST)+1.02x(ALT)+ 0.9x(EF). The age of the patient, the mean Hb and the LVEF were the statistically significant variables at CLRM analysis for the Group B. The formula for the Score B= 1.05x(Age)+1.001x(Hb mean) +0.9x(EF). Finally, Table 5 shows the application of these formulas to the full data set, defining five well-distinguished prognostic categories (Very low, Low, Intermediate, High, Very high). Conclusions Following appropriate validation, we propose that the severity scoring system described here could be developed into a practical tool for widespread clinical application, not only to evaluate patient status and classify disease subgroups, but also to inform treatment decisions and monitor patient progress in response to therapy. Finally, the use of this scoring system may help to select appropriate candidate for innovative treatment. Disclosures Pepe: Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support. Vichinsky:bluebird bio: Consultancy, Research Funding; GBT: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Agios: Consultancy, Research Funding.

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.

BACKGROUND: Transfusion dependency determines iron overload in thalassaemia major, with devastating complications. Significant liver iron overload has been observed from early childhood and we aimed to evaluate factors that could predict liver iron overload at the first magnetic resonance imaging (MRI). MATERIALS AND METHODS: All transfusion-dependent children who underwent MRI to assess iron overload were retrospectively studied. Age, weight, height, blood requirement, chelation drug and dosage, serum ferritin and liver enzymes were evaluated at three specific steps: start of transfusion regimen, start of chelation therapy, and first MRI. RESULTS: Among 198 patients, 25 children met inclusion criteria. No differences were detected in all the assessed parameters at start of transfusion regimen and chelation therapy (p>0.05) between patients with good iron balance (liver iron concentration [LIC] 7). At the first MRI, patients with iron overload had significantly higher serum ferritin (3,080.3±1,078.5 vs 1,672.0±705.3 ng/mL; p1,770 ng/mL was detected as the best threshold for predicting liver iron overload at the first MRI (p=0.0003). CONCLUSION: In order to prevent liver iron overload at the first MRI, children should maintain a stable level of serum ferritin below 1,770 from the start of chelation therapy. However, strict monitoring of growth is mandatory.

Introduction. Despite the increasing of number of patients with Sickle Cell Disease (SCD) in Italy, due to multi-ethnic migratory phenomena, a large percentage of Caucasian sickle population is already present in Italy mainly with b-thal/HbS genotype. Red cell transfusion is one effective treatment for both acute and chronic complications of SCD, while hydroxycarbamide (HC) is used to reduce the frequency of painful vaso-occlusive crises (VOCs) and decrease the need for blood transfusion. Through the National Comprehensive Reference Centers for SCD, the Italian Society of Thalassemia and Hemoglobinopathies (SITE), in collaboration with the Society Italian Transfusion Medicine and Immunohematology (SIMTI) and the Italian Association of Hematology and Pediatric Oncology (AIEOP) conducted a national survey to collect information on different therapeutic approaches used for SCD patients. Aim. To assess therapeutic approaches used a large Italian cohort of patients with SCD, accounting for age, genotype and ethnicity. Patients and Methods. Observational Longitudinal Systemic Multicentre Study (https://clinicaltrials.gov/ct2/show/NCT03397017). Data were collected from 2015 to 2018 through a standard web-based application (www.SITE-italia.org) encrypted by the Central Server. All the SCD patients, treated or not treated, were included in order to identify the overall number and all gave written informed consent. The study was approved by Ethics Committee of Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico of Milan, Italy. Results. Thirty-four centers were involved from 14 Italian regions and 1,579 patients were enrolled (802 male and 777 female; median age 23 years - IQR, 25th-75th 10-41 yrs). Genotype, age and ethnicity distribution are shown in Table 1A. As expected, the median age of non-Caucasian patients, mainly HbSS, is significantly lower than Caucasian ones (p Out of 1,579, 365 SCD patients (23%) did not receive any therapy. Acute transfusion regimen (ATR), Chronic transfusion regimen (CTR) and HC were given in monotherapy, respectively in 160, 226 and 197 patients, or in succession/combination in 631 (Table 1B), distributed throughout genotypes. The main reasons for ATR were acute anemia (384 events) and VOCs (352), followed by acute chest syndrome (ACS; 170), surgery (82), pregnancy (64), splenic sequestration (26), stroke (9); multi-organ failure (MOFs 6) and priapism (5). For CRT, it was acute anemia (306 events) and prevention of VOCs (371), ACS (107), primary stroke prevention (78) and secondary prevention stroke (55), pain HC-resistent (39) and leg ulcers (12). For 275 patients out of 631 it was possible to follow the timing of therapy switching (Table 1C). Of 275 patients, 67.6% switched from ATR/CRT to HC, 2.9% from HC to CRT and 6.5% stopped every therapy. Out of 275 patients, 104 were treated with overlapping therapeutic regimen. Discussion. The significant difference of age in Caucasian and non-Caucasian patients is probably due to the efficacy of the national prevention program of hemoglobinopathies, because the non-Caucasian patients are prevalently born out of Italy. The transfusional approach is similar in HbSS and b°-thal/HbS and b+-thal/HbS patients regarding both ATR and CTR. HbSC genotype needed less therapies(p Summary/Conclusion. The transfusional approach is similar in HbSS, b°-thal/HbS and b+-thal/HbS patients with similar indications, prevalently VOCs and anemia. The significant higher age in Caucasian cohort and the consequent long term follow up could be the cause of variable therapeutic approach observed, however Hydroxycarbamide seemed to be the therapy more frequently used and finally suggested to manage chronic manifestations. Figure. Figure. Disclosures Origa: Apopharma: Honoraria; Novartis: Honoraria; Bluebird Bio: Consultancy; Cerus Corporation: Research Funding. Forni:Apopharma: Other: DSM Board; Celgene: Research Funding; Novartis: Other: travel expenses, Research Funding; Shire: Research Funding; Roche: Consultancy.

Patients with Non-Transfusion-Dependent Thalassemia may require regular transfusion therapy. However, these patients are at risk of developing irregular antibodies, making them untransfusable. Second line treatment usually includes hydroxyurea, which however is not effective in all patients. Other treatment options include thalidomide, which has been reported to be safe and effective in selected patients. We report the case of a patient who experienced improvement of hemoglobin levels and of a part of NTDT related complications, following 36months of continuous therapy with low doses of thalidomide.