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Variant Philadelphia (Ph) chromosome translocations have been reported in 5%-10% of patients with newly diagnosed chronic myeloid leukemia (CML). Variant translocations may involve one or more chromosomes in addition to 9 and 22, and can be generated by 2 different mechanisms, 1-step and 2-step rearrangements, as revealed by fluorescence in situ hybridization. The prognostic significance of the occurrence of variant translocations has been discussed in previous studies. The European LeukemiaNet recommendations do not provide a “warning” for patients with variant translocations, but there is limited information about their outcome after therapy with tyrosine kinase inhibitors. To identify the role of variant translocations in early chronic phase (CP) CML patients treated with imatinib mesylate, we performed an analysis in a large series of 559 patients enrolled in 3 prospective imatinib trials of the Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) Working Party on CML. Variant translocations occurred in 30 patients (5%). Our data show that the presence of variant translocations has no impact on the cytogenetic and molecular response or on outcome, regardless of the involvement of different mechanisms, the number of involved chromosomes, or the presence of deletions. Therefore, we suggest that patients with variant translocations do not constitute a “warning” category in the imatinib era. This study is registered at www.clinicaltrials.gov as NCT00514488 and NCT00510926.

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.

In human β-thalassemia, the imbalance between α- and non–α-globin chains causes ineffective erythropoiesis, hemolysis, and anemia: this condition is effectively treated by an enhanced level of fetal hemoglobin (HbF). In spite of extensive studies on pharmacologic induction of HbF synthesis, clinical trials based on HbF reactivation in β-thalassemia produced inconsistent results. Here, we investigated the in vitro response of β-thalassemic erythroid progenitors to kit ligand (KL) in terms of HbF reactivation, stimulation of effective erythropoiesis, and inhibition of apoptosis. In unilineage erythroid cultures of 20 patients with intermedia or major β-thalassemia, addition of KL, alone or combined with dexamethasone (Dex), remarkably stimulated cell proliferation (3-4 logs more than control cultures), while decreasing the percentage of apoptotic and dyserythropoietic cells (<5%). More important, in both thalassemic groups, addition of KL or KL plus Dex induced a marked increase of γ-globin synthesis, thus reaching HbF levels 3-fold higher than in con-trol cultures (eg, from 27% to 75% or 81%, respectively, in β-thalassemia major). These studies indicate that in β-thalassemia, KL, alone or combined with Dex, induces an expansion of effective erythropoiesis and the reactivation of γ-globin genes up to fetal levels and may hence be considered as a potential therapeutic agent for this disease.

No relevant conflicts of interest to declare.

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.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.We identified 4 groups of patients: group I (17%) with homogeneous MIO (all segments with T2*<20 ms), group II (12%) with heterogeneous MIO (some segments with T2*<20 ms and others with T2*≥20 ms) and global heart T2*<20 ms; group III (29%) with heterogeneous MIO and global heart T2*≥20 ms; group IV (42%) with no MIO (all segments with T2*≥20 ms). The clinically relevant findings in the 4 groups are summarized in Table 1. The percentage of patients with cardiac complications was significantly different in the 4 groups (P<0.0001). In particular, the percentage of patients with heart failure was significantly different in the 4 groups (P<0.0001). No significant differences were found among groups in the percentage of arrhythmias and pulmonary hypertension. Odds Ratio for cardiac complications was 1.7 (1.0–2.7 OR 95% CI; P=0.041) for patients with homogeneous MIO versus patients with no MIO. Odds Ratio for heart failure was 2.3 (1.3–4.2 OR 95% CI; P=0.004) for patients with homogeneous MIO versus patients with no MIO and 2.2 (1.1–4.2 OR 95% CI; P=0.020) for patients with heterogeneous MIO and global heart T2*<20 ms versus patients with no MIO.Homogeneous MIO predicts a significantly higher risk to develop cardiac complications, especially heart failure, suggesting an intensive chelation therapy in this group of patients.No relevant conflicts of interest to declare.

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.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.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<0,0001, Fig. I). Actually, while the Sequential DFP-DFO treatment shows a slight advantage in terms of difference in the mean of LVEF (Coeff. 2,36, 95% CI (0,02; 4,71), p-value=0,047,Fig. I), it does not increase significantly LVEF over the time (Coeff. −0,34, 95% CI (−1,09; 0,39), p-value=0,359).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<0,0001, Fig. 1). Cardioprotective effect of deferiprone on mitochondrial function in cultured, iron-loaded heart cells has been suggested (Link et al., 1999;Glickstein et al., 2006;Xu et al.,2006), even at concentrations below the iron-mobilizing effect (Link et al.,1999). These findings clincally support as long-term treatment with DFP-alone enhances LVEF over the years and may prevent death due to heart failure in patients with thalassemia major.Off Label Use: Deferiprone on sequencial way with Deferoxamine.

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.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.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*<20 ms), in all three groups there was a significant improvement in the global heart T2* value (DFO-DFP: P=0.004, DFP: P=0.015 and DFO: ms P=0.007) and a significant reduction in the number of pathological segments (DFO-DFP: P=0.026, DFP: P=0.012 and DFO: P=0.002). In DFO-DFP and DFP groups there was a significant increment in the left ventricular (LV) ejection fraction (EF) (P=0.035 and P=0.045, respectively) as well as in the right ventricular (RV) EF (P=0.017 and P=0.001, respectively). The improvement in the global heart T2* and in biventricular function were not significantly different in DFO-DFP compared to the other groups (Table 1).Among the patients with hepatic iron at baseline (T2*<9.2 ms), only in DFO group there was a significant improvement in the liver T2* value (2.0±3.5 ms P=0.010). Liver T2*changes were not significantly different in DFO-DFP versus the other groups.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.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.

T2* Magnetic Resonance Imaging (MRI) technique allows noninvasive quantification of organ-specific iron burden, playing a key role in the management of thalassemia major (TM) patients. There are few data on the incidence of heart failure and arrhythmias in TM patients according to baseline T2* values. The aim of this study was to establish prospectively the risk of cardiac complications in a large cohort of well-treated TM patients.We considered 527 TM patients (252 males, mean age 30±9) for who clinical data relative to a period of 5 years after the first MRI were collected in a central data base. At time of the first scan mean ferritin levels were1653±1559 ng/l, global heart was 27±13 ms, and excellent/good level of compliance were present in the 96% of the study population.At 5 years of follow-up, we recorded 24 cardiac events: 4 episodes of cardiac failure, 15 of arrhythmia, 1 of pulmonary hypertension and 4 of other cardiac complications. The majority of these events (21/24) happened within the first 24 months subsequent to the MRI, so we considered this follow-up period. At the first MRI scan, in patients with cardiac complications the global heart T2* was 22.5 ±12.4 ms. In comparison with global heart T2* values ≥20 ms, there was not a significantly increased risk of cardiac complications associated with global heart T2* values <20 ms (HR= 2.028 P=0.09) (see figure). In the heart failure patients the global heart T2* was 19±12 ms. In comparison with global heart T2* values ≥20 ms, there was not a significantly increased risk of heart failure associated with global heart T2* values <20 ms (HR=1.9 P=0.524) or <10 ms (HR=2.6 P=0.443).In the arrhythmic patients the global heart T2* was 25±13 ms. In comparison with global heart T2* values ≥20 ms, there was not a significantly increased risk of arrhythmia associated with global heart T2* values <20 ms (HR=2.1 P=0.179) or <10 ms (HR=0.8 P=0.824). During the follow up changes in the chelation therapy (type and/or dose-frequencies) were found in > 25% of the study population.We detected very few cardiac events, almost all concentrated in the first 24 months. In a large cohort of well-treated TM patients heart T2* lost its power in predicting cardiac events probably due to a patient-specific adjustment of the chelation therapy MRI-guided.No relevant conflicts of interest to declare.

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.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.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*<9.2 ms), only in the DFX group there was a significant improvement in the liver T2* value (2.6±5.3 ms P=0.001). The changes in liver T2* were significantly higher in DFX group than in DFP-DFO (0.5±2.0 ms) group (P=0.030) (Figure 2).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.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.

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.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.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<0,0001,Fig. 1). Patients with a mean reduction of LVEF greater or equal to 7% over the time had a statistical significant higher risk of death from heart failure (OR= 4,93,95% CI 1,61;15,11, p-value = 0,005).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.No relevant conflicts of interest to declare.

Magnetic Resonance Imaging (MRI) by the T2* technique allows highly reproducible and non invasive quantifications of myocardial iron burden and it is the gold standard for quantifying biventricular function parameters. It is important to determine the appropriate age to start MRI screening, because its high cost. Few data are available in the literature and they are contrasting. So the aim of this study was to address this issue in our paediatric patients with thalassemia major (TM).We studied retrospectively 72 patients (47 males, 4.2–17.9 years old, mean age 13.03 ± 3.70 years), enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network. Myocardial iron overload was measured by T2* multislice multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images.The global heart T2* value was 29.7 ± 11.2 ms (range 6.2 – 48.0 ms). No significant correlation was found between global heart T2* value and age (see figure). The global heart T2* value did not show significant differences according to the sex (male 30.2 ± 11.0 ms versus female 28.7 ± 11.8 ms, P=0.568). Sixteen patients (22%) showed an abnormal global heart T2* value (<20 ms) and none of them was under 8 years of age. Global heart T2* value was negatively correlated with mean serum ferritin levels. Odds Ratio for high serum ferritin levels (≥ 1500 ng/ml) was 8.4 (1.01–69.37, OR 95%CI) for abnormal global heart T2* values (< 20 ms). The global heart T2* value did not show a significant difference with respect to the chelation therapy (P=0.322). No significant correlations were found between the global heart T2* values and the bi-atrial areas or the LV and RV morphological and functional parameters. Eight patients showed a left ventricular (LV) ejection fraction (EF) < 57% and none of them was under 7 years of age. Two patients showed a right ventricular (RV) EF < 52% and none of them was under 14 years of age.The MRI screening for both cardiac iron overload and function assessment can be started for TM patients at the age of 7 years. At this age not sedation is generally needed. If the availability of cardiac MRI is low, the serum ferritin levels could be used as a discriminating factor.No relevant conflicts of interest to declare.

In thalassemia major (TM) patients myocardial iron overload and chronic anemia are the recognized leading causes of cardiomyopathy, but a role can also be played by other factors such as endocrine abnormalities. The aim of this retrospective study was to evaluate if diabetes mellitus (DM) was associated with an higher prevalence and risk of cardiac dysfunction and of heart complications, regardless to the presence of myocardial iron overload.From a cohort of 957 TM patients who underwent MRI within the MIOT network (Myocardial Iron Overload in Thalassemia), among the patients (N = 358) with no cardiac iron (all cardiac segments with a T2* ≥ 20 ms) we identified 29 patients with DM and 329 patients without DM. The normal values of ejection fraction (EF) normalized by sex and age, obtained in a cohort of 142 TM patients without cardiac disease and iron overload, were used to define left ventricular (LV) and right ventricular (RV) heart dysfunction (EF < mean – 2 standard deviation). Heart failure (HF) was diagnosed by Magnetic Resonance Imaging (MRI) in presence of a LV and/or RV EF lower than 4 standard deviations from the normalized mean value and by a positive history (clinical symptoms, confirmation by physical examination and treatment). Myocardial fibrosis was evaluated by delayed enhancement MRI technique.The prevalence of overall heart dysfunction (LV, RV or both) was higher in patients with DM (44.8%) versus patients without DM (28.3%), with a P-value very close to the statistically significance (P=0.061). In more details, patients with DM presented significantly more biventricular dysfunction (20.7% vs 7.6%, P=0.016). The prevalence of myocardial fibrosis was significantly higher in the DM patients vs the no DM patients (37.5% vs 19.2 %; P=0.033). Cardiac complications occurred with a significantly higher frequency in patients with DM (55.2% vs 15.5%, P<0.0001). Taking into account each cardiac complication separately, a significant difference between the groups was found in the occurrence of heart failure (27.6% vs 9.4%, P<0.003) and hyperkinetic arrhythmias (34.5% vs 5.2%,P<0.0001), both supraventricular (27.6% vs 4%, P<0.0001) and ventricular (6.9% vs 0.6%, P=0.034). Table 1 shows odds ratios (OR) estimating the relationship between diabetes and cardiac involvement. Among cardiac dysfunctions, only the biventricular forms were significantly positively associated with the diabetes. However, the correction for age caused the loss of the significance. The association between DM and myocardial fibrosis became not significant after the correction for age and endocrine co-morbidity. Patients with DM were significantly more likely to have cardiac complications and the results were not affected by the adjustment for age and/or endocrine co-morbidity. Considering separately each cardiac complication, a significant association was found for HF and hyperkinetic arrhythmias. The association between DM and HF resulted not significant after the correction for age. For the hyperkinetic arrhythmias, the OR remained significant after the correction for age and/or endocrine co-morbidity.In TM patients without myocardial iron DM was significantly associated with the presence of cardiac complications globally considered and hyperkinetic arrhythmias.No relevant conflicts of interest to declare.

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.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.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*<20 ms), in all three groups there was a significant improvement in the global heart T2* values (combination: P=0.001; deferiprone: P=0.015 and desferrioxamine: P=0.007) and a significant reduction in the number of segments with an abnormal T2* value (combination: P=0.004; deferiprone: P=0.012 and desferrioxamine: P=0.002). Only in the deferiprone group there was a significant improvement in the left ventricular (LV) ejection fraction (EF) (P=0.045) while improvement in the right ventricular (RV) EF was significant in both combination (P=0.024) and deferiprone (P=0.001) groups. The changes in the global heart T2* as well as in biventricular function were not significantly different in DFO+DFP versus DFO or DFP groups (Table 1). After correction for influential covariates statistically different at baseline (global heart, age and HIC), the changes in global heart T2* values between the combination and the desferrioxamine groups became statistically different (P=0.014). Among the patients with hepatic iron at baseline (T2*<9.2 ms), the improvement in the liver T2* values was significant in the combination and in the desferrioxamine groups (combination: 4.9±6.0 ms P<0.0001; deferiprone: 2.1±4.8 ms P=0.070 and desferrioxamine: 2.0±3.5 ms P=0.010). The increase in liver T2* values was higher in combination versus deferiprone group, with a P-value near to the statistically significance (P=0.062); after covariates adjustment for the variable statistically different at baseline (serum ferritin) the significance was reached (P=0.043). The increase in liver T2* values was significant higher in combination than in desferrioxamine group (P=0.008), even after covariates adjustment.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.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.

Most deaths in thalassemia major (TM) result from cardiac complications due to iron overload. In thalassaemia available three iron chelation regimes in monotherapy may achieve different changes in cardiac iron and function and liver iron. No data are available in literature about prospective comparisons on cardiac iron and function and liver iron in TM patients treated with deferasirox (DFX) versus deferiprone (DFP) and desferrioxamine (DFO) in monotherapy. Magnetic Resonance (MR) is the unique non invasive suitable technique to evaluated quantitatively this issue. The aim of this multi-centre study was to assess prospectively in the clinical practice the efficacy of the DFX versus DFP and DFO in monoterapy in a large cohort of TM patients by quantitative MR.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 the 193 TM patients who had been received one chelator alone between the 2 MR scans. We identified 3 groups of patients: 80 treated with DFX, 39 treated with DFP and 74 treated with DFO. Myocardial and liver iron concentrations were measured by T2* multislice multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images.The dose of DFX was 26±7 mg/kg/d, DFP was 73±13 mg/kg/d and DFO was 41±6 mg/kg for 5.5 d/wk. Excellent/good levels of compliance were similar in the 3 groups (DFX 99%, DFP 95%; DFO 96%, P = 0.6). Among the patients with no significant myocardial iron overload at baseline (global heart T2* ≥ 20 ms) (DFX 54 pts, DFP 30 pts, DFO 53 pts), there were no significant differences in all 3 groups to maintain the patients without significant myocardial iron overload (DFX 98%; DFP 100%; DFO 98%; P=1.0)Among the patients with myocardial iron overload at baseline (global heart T2* < 20 ms) in all 3 groups there was a significant improvement in the global heart T2* value (DFX P=0.001, DFP P=0.015 and DFO P =0.007) and in the number of segment with a normal T2* value (DFX + 2.4 P=0.003, DFP +6.0 P=0.031 and DFO + 2.9 P=0.001); only in the DFP group there was a significant improvement in the right global systolic function (+ 6.8% P = 0.016). The improvement in the global heart T2* was significantly lower in the DFX versus the DFP group (P=0.0026), but it was not significantly different in the DFX versus the DFO group (mean difference global heart T2* 3.5 ± 4.7 ms versus 8.8 ± 8.6 ms and versus 3.7 ± 5.5 ms, respectively; P = 0.90) (see the figure). The changes in the mean serum ferritin level and in the global systolic bi-ventricular function were not significantly different among groups.In patients with liver iron overload at baseline (liver T2* < 5.1 ms), the change in the liver T2* was not significant among groups (mean difference liver T2*DFX 2.1 ± 4.2 ms vs DFO 1.9 ± 3.8 ms vs DFP 1.3 ± 3.3 ms; P = 0.9).Prospectively over 15 months in a large clinical setting of TM patients DFP monotherapy was significantly more effective than DFX in improving myocardial siderosis, no significant differences were found between DFX and DFO monotherapy.No relevant conflicts of interest to declare.

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 deferiprone–deferoxamine (DFP-DFO) versus deferasirox (DFX). Magnetic Resonance (MR) is the unique non invasive suitable technique to evaluated quantitatively this issue. The aim of this multi-centre study was to assess prospectively in the clinical practice the efficacy of the DFP-DFO vs DFX in a cohort of TM patients by quantitative MR.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 44 patients treated with DFX between the 2 MR scans. Myocardial and liver iron concentrations were measured by T2* multislice multiecho technique.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 DFX was 26±6 mg/kg/d. Excellent/good levels of compliance were similar in the 2 groups (DFP-DFO 96% vs DFX 100%; P = 0.36). At baseline the 2 groups were homogeneous for cardiac and liver iron. Among the patients with no significant myocardial iron overload at baseline (global heart T2* 3 20 ms), there were no significant differences between groups to maintain the patients without myocardial iron overload (DFP-DFO 95% vs DFX 96%; P = 1.0). Among the patients with myocardial iron overload at baseline (global heart T2* < 20 ms), only in the DFX group there was a significant improvement in the global heart T2* value (11 ± 5 ms at baseline versus 16 ± 8 at 18 ± 3 months, P = 0.0001) and in the number of segment with a normal T2* value (P = 0.003). The improvement in the global heart T2* was not significantly difference in the DFP-DFO versus the DFX group (mean difference global heart T2* 2.2 ± 4.1 ms versus 4.6 ± 4.8 P = 0.2). The changes in the mean serum ferritin level were not significantly different between groups. In patients with liver iron overload at baseline (liver T2* < 5.1 ms), the change in the liver T2* was not significant between groups (mean difference liver T2* 0.9 ± 2.1 ms vs 2.4 ± 5.2; P = 0.3).Prospectively in the clinical setting over 15 months we did not find significant differences on cardiac and liver iron by quantitative MRI in TM patients treated with sequential DFP–DFO versus the TM patients treated with DFX.No relevant conflicts of interest to declare.

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

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

Segmental distribution of T2* values can be assessed in heart iron overloaded patients by multislice, multiecho cardiovascular MRI. A significant heterogeneity in T2* segmental distribution was demonstrated in previous studies in thalassemia major (TM) patients [1] and may represent true heterogeneous iron density or could be generated by geometric and susceptibility artefacts. In this study we investigate the relationship between T2* heterogeneity and iron overload progression in a large patient population in order to understand if susceptibility artefact may account for inhomogeneous T2* values segmental distribution. 230 TM patients consecutively affered to our laboratory were studied. Informed consent was obtained for all of them. MRI was performed using a 1.5 T MR scanner (GE Signa, CV/i). For the measurements of myocardial T2*, a fast gradient echo-multiecho sequence (FA=25°, matrix=256×192, FOV=35×35 cm, thickness=8.0 mm, NEX=0.75) was used with ECG triggering. Each slice was acquired at nine echo times (2.2–20.3 ms, with echo spacing of 2.26 ms) in a single end-expiratory breath-hold. Three short axis views (basal, medium, and apical) of the left ventricle were obtained and analyzed using a custom-written, previous validated software (HIPPO MIOT®) The myocardium was automatically segmented into a 16-segments standardized heart model and the T2* value on each segment was calculated as well as the global T2* value. The level of heterogeneity of the T2* segmental distribution on each patient was evaluated by computing the coefficient of variation (CoV) as the standard deviation of the absolute value of differences between the segmental T2* values and the global T2* value divided by their means, and expressed as the percentage. A surrogate data sets was obtained stating that the inhomogeneous segmental distribution of T2* would be generated only by susceptibility artefacts that are additive in the R2* (1/T2*) domain. These artefacts were characterized in a previous study by the analysis of the segmental T2* distribution in normal subject [2]. In 45 (20%) TM patients, segmental T2* values were all below the lower limit of normal (20 ms). In 104 (45%) patients, T2* values were heterogeneous with respect to the normal threshold. Of these patients, 74% showed a normal T2* global value. Eighty-one (35%) patients had all normal segments. Figure 1 shows the distribution of heterogeneous T2* among the patients population. Figure 2 shows the CoV in myocardial T2* distribution vs. the global T2* values in patients and surrogate data. Patients were sorted using the global T2* values and averaged on a 20-point window to smooth the resulting graph. Mean and normal global T2* value for healthy subjects were assessed in a previous study. Montecarlo simulation was performed on 10,000 surrogate data sets. For surrogate data, the mean CoV values together with the mean⊠2SD limits are shown. T2* heterogeneity for patients without iron overload was compatible with the hypothesis that the heterogeneity was generated by additive susceptibility artefacts. Below the normal limit of global T2* the heterogeneity abruptly increased of about 10%. Starting from this level, the heterogeneity decreased linearly returning to 25% in patients with high iron overload levels. Figure 2 shows In conclusion, a large percentage of thalassemia major patients shows a significant heterogeneity of segmental distribution of T2* values in myocardium, measured by multislice multiecho T2* cardiac magnetic resonance. T2* segmental heterogeneity in TM patients cannot be explained by the effect of susceptibility artefacts, that are additive and should vanish at high iron overload levels. A possible interpretation is that a true heterogeneity in iron overload distribution is present in TM patients. This heterogeneity seems more important in the early development of iron overload and reduces when the iron overload level increases. Figure 1 Figure 1. Figure 2 Figure 2.

Intensive chemotherapy significantly improves the outcome of pediatric acute lymphoblastic leukemia (ALL) but unfortunately increases the incidence and severity of acute adverse events. The current study analyses the incidence of central nervous system (CNS) complications during ALL treatment in a single pediatric institution. CNS leukemic infiltration at diagnosis, therapy-related peripheral neuropathy and leukoencephalopathy and neurocognitive defects after treatment were excluded by the study. From September 2000 to July 2008, two hundred and forty ALL patients (pts) were treated in our Institution according to BFM-AIEOP ALL 2000 protocol. Twenty-four out of 240 patients (10 %) (15 females and 9 males, median age at the event 7.7 years, range 2–16 years) developed CNS complications during treatment. Thirteen presented tonic-clonic seizures, four showed dyskinesia and dyslalia, one presented visual impairment and enuresis, and six had loss of consciousness. In 18 pts a rapid resolution of the event was obtained by administration of benzodiazepines or barbiturates; 6 pts required admission in intensive care unit, instead. Only two out of twenty-four patients presented neurological sequelae (one pts with recurrent seizures and one pts with right limb disability). Co-morbidity at the time of neurological accident included: blood pressure increase (6 pts), electrolytes imbalance (4 pts), LDH increase (4 pts), coagulation disorders (6 pts), hepatic enzyme increase (2 pts), severe anemia (1 pts), severe thrombocytopenia (4 pts), renal failure (1 pts), and Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) (1 pts). Radiological scanning (either CT or MRI) and electroencephalography (EEG) performed within 48 hr from the onset of the clinical symptoms revealed different etiologies: 8 posterior reversible leukoencephalopathies (PRES), 3 cerebral bleedings, 2 ischemic cerebral diseases, 2 methotrexate toxicity, 1 SIADH, 2 temporal lobe epilepsy and 6 unidentified problems. In conclusion this retrospective study on CNS complications during ALL treatment shows that the most frequent neurological accident (33%) is the PRES.

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

Iron induced cardiomiopathy is the main cause of mortality in thalassemic population. Thus, the improvement of chelation regimens, to reduce cardiac disease, has the highest priority. Efficient evaluation of cardiac iron status and careful epidemiologic assessment of thalassemic patients play an important role in this matter. T2* magnetic resonance imaging (MRI) is a unique technique to quantify myocardial iron overload and useful to tailor the chelation therapy. Effective and reproducible assessment of myocardial iron loading using the multislice multiecho T2* approach for segmental and global myocardial iron distribution, has been demonstrated at the MRI centre in Pisa [1,2]. Aim of this work is to build within the MIOT (Myocardial Iron Overload in Thalassemia) project a reliable network of haematological and paediatric centers specializing in thalassemia care and MRI centers able to perform feasible and reproducible heart and liver iron overload assessments for a consistent number of thalassemia patients in a standardized and robust manner. First, the transferability of the multislice multiecho T2* technique was assessed. Heart multislice multiecho T2* and liver multiecho T2* sequences were installed on 1.5 T MRI scanners (GE Healthcare) at six different sites in Italy. Five healthy subjects at each site (n=30) were scanned to verify the homogeneity of normal ranges (T2* lover limit of normal 20ms). Then, five thalassemia major (TM) patients were scanned at the reference site and were rescanned locally (n=25) within one month. T2* images were analysed using a previously validated software (HIPPO MIOT®). T2* values of healthy subjects showed inter-sites homogeneity. On TM patients, for global heart T2* values the correlation coefficient was 0.97, Coefficients of Variation (CoVs) ranged from 0.04 to 0.12 and Intraclass Coefficients (ICCs) ranged from 0.94 to 0.99. The mean CoV and ICC for segmental T2* distribution were 0.198 and 88, respectively. After the assessment of MRI technique reproducibility, patients enrolling started in September 2006. Since the project’s beginning, 695 thalassemia patients have been involved in the network. Six hundred and thirteen patients (88%) successfully underwent MRI examination. Each MRI center had a specific absorption capacity that seemed to remain constant over time, but the network was capable of sustaining an increasing number of patients due to continuous enrolment of new centers. The mean distance from the patients’ home locations to the MRI centers where the patients underwent the exams, which is considered an indicator of patient comfort, significantly decreased during the network’s evolution. In Figure, the average distances from the thalassemia centers which sent the patients for MRI examination are plotted versus time. With the activation of delocalized MRI centers, average distances tend to be comparable. In conclusion, the multislice multiecho T2* technique is transferable among scanners with good reproducibility. The MIOT network seems to be a robust and scalable system in which T2* MRI-based cardiac and liver iron overload assessment is available, accessible and reachable for a significant and increasing number of thalassemia patients in Italy, reducing the mean distance from the patients’ locations to the MRI sites. A solid, wide and homogeneous database will constitute an important scientific resource, shortening the time scale for diagnostic, prognostic and therapeutical evidence-based research on the management of thalassemia disease. Figure Figure

Despite dramatic gains in life expectancy in the desferrioxamine era for thalassemia major patients, the leading cause of death for this young adult's population remains iron-induced heart failure. For this reason, strategies to reduce heart disease by improving chelation regimens have the highest priority in this phase. These strategies include development of novel oral iron chelators to improve compliance. Oral deferipron was proved more effective than subcutaneous desferrioxamine in removing cardiac iron. The novel oral one-daily chelator deferasirox has been recently commercially available but its long-term efficacy on myocardial iron concentrations and cardiac function is unknown. Aim of this study was to compare in thalassemia major patients the effectiveness of deferasirox, deferipron, and desferrioxamine on myocardial and liver iron concentrations and bi-ventricular function by quantitative magnetic-resonance imaging (MRI).

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 <0.01), respectively. The greater mean serum ferritin reduction of sequential L1- DFO treatment was also confirmed all over the study (2° year L1 106 ± 713, L1-DFO -321 ± 92 (p <0.01); 3° year L1 137 ± 137, L1-DFO -292 ± 117 (p <0.05); 4° year L1 216 ± 200, L1-DFO-230 ± 170 (p <0.01); 5° year L1 336 ± 244, L1-DFO -598 ± 203 (p <0.01)). After one-year treatment this sequential group showed greater efficacy in term of serum ferritin levels reduction (−409 ± 64.2) in comparison with the DFO alone arm (−232 ± 619) of a previous randomised multicenter clinical trial in which a comparable cohort of patients were studied (p<0.05). Reversible leukocytopenia was shown in 8 (11.5%) L1 and in 7 (9.8%) sequential L1-DFO treated patients. No agranulocythosis was reported on sequential L1-DFO treated patients during the 5 years study. Hypertransaminasemia developed in 13 (18.8%) L1 and in 5 (7%) sequential L1-DFO treated patients. No other major side effects have been reported. Discontinuation of treatment was necessary in 55.6% L1 and in 57.7% sequential L1-DFO treated patients (chi2 0.03, p=0.86). The failures of treatment were less in sequential L1-DFO arm (n°2) in comparison to L1 alone arm (n°8), although this difference not so far reached the statistical significance (chi2 3.4, p=0.06). These findings suggest that sequential L1-DFO treatment in a long-term study is more effective than L1 alone with milder and reversible side effects. Moreover, its efficacy is also higher in comparison with DFO alone at short-term evaluation. 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

We conducted a 4-yr prospective trial to evaluate the long-term effects of combined deferiprone (DFP)/deferoxamine (DFO) on reversal of cardiac complications in thalassemia major compared to those of DFO alone. Twenty-eight patients (pts) with cardiac disease requiring medication were stratified according to their risk for cardiac death. Fourteen pts were high risk, serum ferritin (SF) > 2500 ug/L on two-thirds of occasions since the onset of cardiac disease. Of those with a SF < 2500 ug/L (low risk), six had progressive decrements of left ventricular ejection fraction (LVEF). Nine high-risk pts and six low-risk pts were placed on DFP/DFO (DFP, 75 mg/kg/d divided t.i.d.; DFO, 40 – 50 mg/kg over 8 – 12 h at night 5 – 7 d/wk. The others infused DFO alone. If SF fell below 500 ug/L, DFO infusions were reduced to 2 d/wk. Cardiac follow-up (including blood work and ECG) was done at 4-m intervals. M-mode and two-dimensional echocardiograms were done at 4- to 6-m intervals. Cardiac T2* was not available at the beginning of the study. All but eight patients (3 death, 1 refusal, 2 claustrophobic, 2 pacemaker) subsequently had at least one T2* assessment. Routine lab tests were done at 1- to 6-m intervals. Blood counts were done at 7- to 10-d intervals for those taking DFP. Mean follow-up was approximately 40 m. Compliance with DFO was significantly better among low-risk pts in both treatment groups (DFP/DFO, 82% vs 61%; DFO alone, 83% vs 52%) as was that with DFP (94% vs 76%). At baseline, no statistically significant differences were observed between the SF levels, LVEFs or left ventricular shortening fractions (LVSFs) of pts on DFP/DFO or DFO alone in either risk group except for the LVEFs of the low-risk group (DFP/DFO, 56.5% +/− 5.5%; DFO alone, 65.4% +/− 5.0%; p = 0.032). In the high-risk group, four cardiac events (3 deaths, 1 worsening of CHF) occurred in the group getting DFO alone vs none in the DFP/DFO-treated group. The latter pts showed a decrease in SF and an increase in both LVEF and LVSF at the end of study (EOS). The three pts who died (at 17 to 35 m) had increased SFs. These pts were not rescued by IV DFO (98 +/− 12 mg/kg/d). The two DFO-treated pts who survived had marginally improved T2*s (1.5 to 3.0 ms and 7.6 to 8.8 ms) over the year prior to EOS. Only one of the seven evaluable pts on DFP/DFO had a T2* < 10 ms, the others averaging 19.4 +/− 6.7 ms. Among the low-risk pts, those on DFP/DFO showed a reduction in SF and an improvement in both LVEF and LVSF. Those on DFO alone had increased SF but essentially no change in LVEFs or LVSFs. Five pts on DFP/DFO had T2* evaluations. In two pts, T2* rose from 9.0 to 37 ms (38 m) and from 9.3 to 11.8 ms (17 m). The remaining three had T2* values > 20 ms at EOS. Similar results were seen in low-risk pts on DFO alone. These finding clearly support the notion that DFP/DFO has a beneficial effect upon the heart, even in well established disease. Moreover, our finding of low T2* values associated with low SF levels indicates the importance of tailoring treatment to each individual.

Background: CD is a rare entity characterized by unicentric or multicentric clinical presentation. Three histologic variants (hyline vascular, plasmacell and mixed) have been described. Coexistence of CD and non-Hodgkin (NHL) and Hodgkin’s (HL) lymphomas is well documented in literature; however the last type of association is a rare event. When it occurs, the most frequent association is between interfollicular subtype of HL and plasmacell variant of CD, while there is no agreement regarding a more common combination of HL and either the multicentric or the localized form of CD. Methods and Results: On July 2000, a 33-years-old woman HIV-negative was found to be affected by NS grade I of BNLI cHL diagnosed on a supraclavear nodal biopsy. The final stage was IIIA. After 6 cycles of ABVD and mediastinal radiotherapy, the patient obtained a CR (January 2001). One year later (May 2002) she complained asthenia, but not other clinical signs or symptoms. Laboratory tests revelead increased ERS (49 mm/h) and only mild anemia (11,7 mg/dl). Computerized tomography (CT), ultrasonography (US) and positron emission tomography (PET) showed multiple subdiaphgramatic enlarged lymphnodes in celiac tripod region, haepatoduodenal ligament and interaortocaval zone (2–3 cm of diameter). However, the biopsied nodes obtained by laparoscopy reveled a mixed reactive lymphoadenopathy, but not recurrent HL. During the following 13 months of observation, a further reduction in the hemoglobine value (10.9 mg/dl), increased ERS (87 mm/h) and a very slowly progressive increase in the dimension (4–5 cm diameter) of the abdominal enlarged nodes were documented in the absence of others clinical signs or symptoms. A second nodal biopsy (paracaval lymphnode) was performed in October 2003. Histology showed some lymphoid follicles with small germinal centers(GC), which presented prominent hyalinized vessels and politypical plasmacell component in interfollicular areas indicative of CD (mixed hyaline-vascular and plasmacell subtype). Rare Reed-Stenberg and lacunar cells were found in this background. After the second course of chemoterapy (6 cycles of ABVD) a rapid normalization of ERS and anemia were documented. The CT findings showed a reduction of size and numbers, but no disappereance of abdominal lymph nodes (4 residual nodes of 1–2 cm of diameter). A further nodal biopsy was performed, which confirmed the persistence of HL in the background of CD. Only after RT, the patient obtained a second CR as documented by two subsequent negative CT and PET scans. On July 2005, even if laboratory tests were normal, a single ipogastric superficial lymphadenopathy was detected on phisical examination and confirmed by US: so, a new diagnostic work-up, consisting of PET-SCAN and escixional biopsy is ongoing. Conclusion: After cHL sclero-nodular type, the diagnosis of recurrent HL probably arising on a preexisting multifocal CD, both caracterized by a particularly indolent course, was documented. The two pathogenetic mechanisms hypothized for CD and HL association are: secretion of IL-6 by Hodgkin’s RS cells and/or histiocytes or manifestation of an abnormal immune state associated with Hodgkin’s disease.

Incidence of Pulmonary Hypertension (PH) has been described in haemoglobinopathic patients, ranging from 10% to 50%, depending on age, therapy, coexisting left ventricular dysfunction (LVD) and classification of the disease. To determine whether PH can occurs in haemoglobinopathic patients in absence of overt LVD, we studied 1121 pts from 7 Thalassemia Centers in Italy(485 Thalassemia Major (TM), 458 thalassemia intermedia (TI), 178 Sickle Cell or Sickle Thalassemia Disease (SCD),49% males, mean age 30 yrs, range 13–56 yrs). In all pts echocardiographic (Echo) defined ejection fraction (EF%) was > 45% and clinically overt LVD was excluded. A cross-sectional Echo study was performed in order to detect PH that was prospectively defined as mild with tricuspid regurgitant jet velocity (TRV)of at least 2.5 m per second and defined as severe with a TRV> 3.5 m per second. Severe PH was observed in 9 pts, 3 with TM, in 6 with TI and in 1 patients with SCD. Mild PH occurs in 46 patients with TM, in 57 patients with TI and 11 pts with SCD. In the remaining patients, PH was in the normal range (TM 89,9%, TI 86,2% and SCD 93,2% of pts, respectively). In the whole group of hemoglobinopathic pts the incidence of PH (mild plus severe) range from 6.5 % to 13.8% of pts. PH (mild to severe) particularly affects pts with TI (13,8% of pts). Incidence of PH in TM, TI and SCD Tricuspid Regurgitant Jet Velocity Thal Major 485 pts Thal Int 458 pts SCD 178 pts % pts TRV<2.5 m/sec 436 (89.9%) 395 (86.2%) 166 (93.2%) 89% 2,53.5 m/sec 3 (0.6%) 6 (1.3%) 1 (0.9%) 0.9% Our data support a significant presence of PH in haemoglobinopathic pts (6.2 to 13,8%) even though well treated and without LVD. Considering the pathophisiology of haemoglobinopathies a specific consideration to PH in these diseases is required in order to establish a preventive and therapeutic approach.

Background and aims Present data indicate that FDG-PET has a superior accuracy than gallium scan (Ga-S) in staging and post-therapy restaging of malignant lymphomas. However in Hodgkin’s lymphoma (HL) with a predominant mediastinal involvement and in primary mediastinal lymphoma (ML), this latter, less expensive, nuclear imaging technique might still have a diagnostic value. The aims of this prospective study were to assess: the accuracy of SPET Ga-S in detecting residual tumour in the upper diaphragm nodal regions mainly in the mediastinal site and its predictive value in terms of disease free survival (DFS) and overall survival (OS). Methods Since 1989, 68 patients (pts) with HL (60) or ML (8) were enrolled: 24 male and 44 female. Median age was 28 (range 12-80) years. Ann Arbor stage distribution was: stage IIA in 18 pts, IIB in 23 pts, IIIA in 4 pts, IIIB in 6 pts, IVA in 4 pts and IVB in 13 pts. Histology subgroups included 43 SN, 11 CM, 1 DL, 2 LP, 3 unclassified HL and 8 large B-cell ML. Bulky mediastinal disease was detected in 22 HL and all of ML cases. 44 patients received conventional chemotherapy, 4 non-myeloablative and 20 myeloablative chemotherapy with peripheral blood stem cells support because of unfavourable disease or resistant or relapsing to primary treatment disease. Ga-SPET was performed in all patients 72 hours after the intravenous injection of 370 MBq (8–10 mCi) of 67Ga cirate. SPET data acqusiton included a 360° rotation, with 60 projections at rate of 20 s per projection. The matrix size was 64x64 and a Butterworth filter (0.4–0.6) was used. Results A total of 107 Ga-SPET/TC restaging were obtained after chemotherapy and/or chemo-radiotherapy completion in 64/68 evaluable pts. Despite 84/107 CT evaluations were suggestive of persistent disease in the mediastinal region, 61/107 simultaneous Ga-SPET exams were negative. Instead Ga-SPET indicated the presence of active disease only in 5 cases although the CT was interpreted as negative. Concordant results were documented in the remaining 41 evaluations. The difference in the final post-therapy findings between Ga-SPET and TC were less frequent in upper diaphragm nodal region other than mediastinum, with concordant and discordant results respectively in 51/71 and 20/71 scans. Sensitivity, specificity and accuracy were 89%, 93% and 92% for the Ga-SPET, while they were 100%, 27% and 37% for the CT when the mediastinal area was considered. After a median follow-up of 34 (4–138) months, DFS and OS for patients with a positive Ga-SPET at the end of treatment program were 9 (2–57) and 24,5 (9–67) months, respectively. In contrast, the Corresponding figures have not been reached for patiens with a negative Ga-SPET after a median time of 31,5+ (3–136) months and 49,5+ (4–144) monhs respectively. The median values of DSF and OS of patients with a CT compatible with absent or persistent disease have not been reached at 31+ (3–89) vs 27+ (3–136) months and 46+ (11–108) vs 40+ (4–144) months. Conclusions Thus, Ga-SPET is still a useful, sensitive and not expensive method to determine the presence of eventual active post-therapy disease in the mediastinum.