Risk factors for endocrine complications in transfusion-dependent thalassemia patients on chelation therapy with deferasirox: a risk assessment study from a multi-center nation-wide cohort.

Transfusion-dependent patients typically develop iron-induced cardiomyopathy, liver disease, and endocrine complications. We aimed to estimate the incidence of endocrine disorders in transfusiondependent thalassemia (TDT) patients during long-term iron-chelation therapy with deferasirox (DFX). We developed a multi-center follow-up study of 426 TDT patients treated with once-daily DFX for a median duration of 8 years, up to 18.5 years. At baseline, 118, 121, and 187 patients had 0, 1, or ≥2 endocrine diseases respectively. 104 additional endocrine diseases were developed during the follow-up. The overall risk of developing a new endocrine complication within 5 years was 9.7% (95% Confidence Interval [CI]: 6.3-13.1). Multiple Cox regression analysis identified three key predictors: age showed a positive log-linear effect (adjusted hazard ratio [HR] for 50% increase 1.2, 95% CI: 1.1-1.3, P=0.005), the serum concentration of thyrotropin showed a positive linear effect (adjusted HR for 1 mIU/L increase 1.3, 95% CI: 1.1-1.4, P<0.001) regardless the kind of disease incident, while the number of previous endocrine diseases showed a negative linear effect: the higher the number of diseases at baseline the lower the chance of developing further diseasess (adjusted HR for unit increase 0.5, 95% CI: 0.4-0.7, P<0.001). Age and thyrotropin had similar effect sizes across the categories of baseline diseases. The administration of levothyroxine as a covariate did not change the estimates. Although in DFX-treated TDT patients the risk of developing an endocrine complication is generally lower than the previously reported risk, there is considerable risk variation and the burden of these complications remains high. We developed a simple risk score chart enabling clinicians to estimate their patients' risk. Future research will look at increasing the amount of variation explained from our model and testing further clinical and laboratory predictors, including the assessment of direct endocrine magnetic resonance imaging.

Longitudinal follow-up of patients with thalassaemia intermedia who started transfusion therapy in adulthood: a cohort study.

We longitudinally evaluated the effects of regular blood transfusions (BTs), in the real-life context of the Myocardial Iron Overload in Thalassaemia network, in patients with thalassaemia intermedia (TI). We considered 88 patients with TI (52 females) who started regular BTs after the age of 18 years. Magnetic resonance imaging was used to quantify iron overload and biventricular function. For 56·8% of the patients there were more than two indications for the transition to regular BTs, with anaemia present in 94·0% of the cases. A significant decrease in nucleated red blood cells, platelets, lactate dehydrogenase, bilirubin, and uric acid levels was detected 6 months after starting regular BTs. After the transition to the regular BT regimen there was a significant increase only in the frequency of hypothyroidism and osteopenia, and a significant decrease in liver iron and cardiac index. The percentage of chelated patients increased significantly after starting regular BTs. The decision to regularly transfuse patients with TI may represent a way to prevent or slow down the natural progression of the disease, despite the more complex initial management.

The effect of desferrioxamine chelation versus no therapy in patients with non transfusion-dependent thalassaemia: a multicenter prospective comparison from the MIOT network.

We prospectively assessed by magnetic resonance imaging (MRI) the advantages of desferrioxamine (DFO) with respect to the absence of chelation therapy in non transfusion-dependent thalassaemia (NTDT) patients. We considered 18 patients non-chelated and 33 patients who received DFO alone between the two MRI scans. Iron overload was assessed by the T2* technique. Biventricular function parameters were quantified by cine sequences. No patient treated with DFO had cardiac iron. At baseline, only one non-chelated patient showed a pathological heart T2* value (< 20 ms) and he recovered at the follow-up. The percentage of patients who maintained a normal heart T2* value was 100% in both groups. A significant increase in the right ventricular ejection fraction was detected in DFO patients (3.48 ± 7.22%; P = 0.024). The changes in cardiac T2* values and in the biventricular function were comparable between the two groups. In patients with hepatic iron at baseline (MRI liver iron concentration (LIC) ≥ 3 mg/g/dw), the reduction in MRI LIC values was significant only in the DFO group (- 2.20 ± 4.84 mg/g/dw; P = 0.050). The decrease in MRI LIC was comparable between the groups. In conclusion, in NTDT patients, DFO therapy showed no advantage in terms of cardiac iron but its administration allowed an improvement in right ventricular function. Moreover, DFO reduced hepatic iron in patients with significant iron burden at baseline.

The era of comparable life expectancy between thalassaemia major and intermedia: Is it time to revisit the major-intermedia dichotomy?

In the last few decades, the life expectancy of regularly transfused ß-thalassaemia major (TM) patients has dramatically improved following the introduction of safe transfusion practices, iron chelation therapy, aggressive treatment of infections and improved management of cardiac complications. How such changes, especially those attributed to the introduction of iron chelation therapy, improved the survival of TM patients to approach those with ß-thalassaemia intermedia (TI) remains unknown. Three hundred and seventy-nine patients with TM (n = 284, dead 40) and TI (n = 95, dead 13) were followed retrospectively since birth until 30 June 2015 or death. Kaplan-Meir curves showed statistically significant differences in TM and TI survival (P < 0·0001) before the introduction of iron chelation in 1965, which were no longer apparent after that date (P = 0·086), reducing the Hazard Ratio of death in TM compared to TI from 6·8 [95% confidence interval (CI) 2·6-17·5] before 1965 to 2·8 (95% CI 0·8-9·2). These findings suggest that, in the era of iron chelation therapy and improved survival for TM, the major-intermedia dichotomy needs to be revisited alongside future directions in general management and prevention for both conditions.

Real-life experience with liver iron concentration R2 MRI measurement in patients with hemoglobinopathies: baseline data from LICNET.

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 ß-thalassemia major [TM], 102 ß-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.

Extramedullary hematopoiesis is associated with lower cardiac iron loading in chronically transfused thalassemia patients.

The aim of this study was to evaluate, in a large cohort of chronically transfused patients, whether the presence of extramedullary hematopoiesis (EMH) accounts for the typical patterns of cardiac iron distribution and/or cardiac function parameters. We retrospectively selected 1,266 thalassemia major patients who had undergone regular transfusions (611 men and 655 women; mean age: 31.3 ± 8.9 years, range: 4.2-66.6 years) and were consecutively enrolled within the Myocardial Iron Overload in Thalassemia network. The presence of EMH was evaluated based on steady-state free precession sequences; cardiac and liver iron overloads were quantified using a multiecho T2* approach; cardiac function parameters and pulmonary diameter were quantified using the steady-state free precession sequences; and myocardial fibrosis was evaluated using the late gadolinium enhancement technique. EMH was detected in 167 (13.2%) patients. The EMH+ patients had significantly lower cardiac iron overload than that of the EMH- patients (P = 0.003). The patterns of cardiac iron distribution were significantly different in the EMH+ and EMH- patients (P < 0.0001), with a higher prevalence of patients with no myocardial iron overload and heterogeneous myocardial iron overload and no significant global heart iron in the EMH+ group EMH+ patients had a significantly higher left ventricle mass index (P = 0.001) and a significantly higher pulmonary artery diameter (P = 0.002). In conclusion, in regularly transfused thalassemia patients, EMH was common and was associated with a thalassemia intermedia-like pattern of cardiac iron deposition despite regular transfusion therapy.

Hepatocellular carcinoma in thalassaemia: an update of the Italian Registry.

The risk of developing hepatocellular carcinoma (HCC) in patients with thalassaemia is increased by transfusion-transmitted infections and haemosiderosis. All Italian Thalassaemia Centres use an ad hoc form to report all diagnoses of HCC to the Italian Registry. Since our last report, in 2002, up to December 2012, 62 new cases were identified, 52% of whom were affected by thalassaemia major (TM) and 45% by thalassaemia intermedia (TI). Two had sickle-thalassaemia (ST). The incidence of the tumour is increasing, possibly because of the longer survival of patients and consequent longer exposure to the noxious effects of the hepatotropic viruses and iron. Three patients were hepatitis B surface antigen-positive, 36 patients showed evidence of past infection with hepatitis B virus (HBV). Fifty-four patients had antibodies against hepatitis C virus (HCV), 43 of whom were HCV RNA positive. Only 4 had no evidence of exposure either to HCV or HBV. The mean liver iron concentration was 8 mg/g dry weight. Therapy included chemoembolization, thermoablation with radiofrequency and surgical excision. Three patients underwent liver transplant, 21 received palliative therapy. As of December 2012, 41 patients had died. The average survival time from HCC detection to death was 11·5 months (1·4-107·2 months). Ultrasonography is recommended every 6 months to enable early diagnosis of HCC, which is crucial to decrease mortality.

Cardiac complications and diabetes in thalassaemia major: a large historical multicentre study.

The relationship between diabetes mellitus (DM) and cardiac complications has never been systematically studied in thalassaemia major (TM). We evaluated a large retrospective historical cohort of TM to determine whether DM is associated with a higher risk of heart complications. We compared 86 TM patients affected by DM with 709 TM patients without DM consecutively included in the Myocardial Iron Overload in Thalassaemia database where clinical/instrumental data are recorded from birth to the first cardiovascular magnetic resonance (CMR) exam. All of the cardiac events considered were developed after the DM diagnosis. In DM patients versus non-DM patients we found a significantly higher frequency of cardiac complications (46.5% vs. 16.9%, P < 0.0001), heart failure (HF) (30.2% vs. 11.7%, P < 0.0001), hyperkinetic arrhythmias (18.6% vs. 5.5%, P < 0.0001) and myocardial fibrosis assessed by late gadolinium enhancement (29.9% vs. 18.4%, P = 0.008). TM patients with DM had a significantly higher risk of cardiac complications [odds ratio (OR) 2.84, P < 0.0001], HF (OR 2.32, P = 0.003), hyperkinetic arrhythmias (OR 2.21, P = 0.023) and myocardial fibrosis (OR 1.91, P = 0.021), also adjusting for the absence of myocardial iron overload assessed by T2* CMR and for the covariates (age and/or endocrine co-morbidity). In conclusion, DM significantly increases the risk for cardiac complications, HF, hyperkinetic arrhythmias and myocardial fibrosis in TM patients.

Serial echocardiographic left ventricular ejection fraction measurements: a tool for detecting thalassemia major patients at risk of cardiac death.

Cardiac damage remains a major cause of mortality among patients with thalassemia major. The detection of a lower cardiac magnetic resonance T2* (CMR-T2*) signal has been suggested as a powerful predictor of the subsequent development of heart failure. However, the lack of worldwide availability of CMR-T2* facilities prevents its widespread use for follow-up evaluations of cardiac function in thalassemia major patients, warranting the need to assess the utility of other possible procedures. In this setting, the determination of left ventricular ejection fraction (LVEF) offers an accurate and reproducible method for heart function evaluation. These findings suggest a reduction in LVEF≥7%, over time, determined by 2-D echocardiography, may be considered a strong predictive tool for the detection of thalassemia major patients with increased risk of cardiac death. The reduction of LVEF≥7% had higher (84.76%) predictive value. Finally, Kaplan-Meier survival curves of thalassemia major patients with LVEF≥7% showed a statistically significant decreased probability of survival for heart disease (p=0.0022). However, because of limitations related to the study design, such findings should be confirmed in a large long-term prospective clinical trial.

Long-term treatment with deferiprone enhances left ventricular ejection function when compared to deferoxamine in patients with thalassemia major.

Transfusion and iron chelation treatment have significantly reduced morbidity and improved survival of patients with thalassemia major. However, cardiac disease continues to be the most common cause of death. We report the left-ventricular ejection fraction, determined by echocardiography, in one hundred sixty-eight patients with thalassemia major followed for at least 5years who received continuous monotherapy with deferoxamine (N=108) or deferiprone (N=60). The statistical analysis, using the generalized estimating equations model, indicated that the group treated with deferiprone had a significantly better left-ventricular ejection fraction than did those treated with deferoxamine (coefficient 0.97; 95% CI 0.37; 1.6, p=0.002). The heart may be particularly sensitive to iron-induced mitochondrial damage because of the large number of mitochondria and its low level of antioxidants. Deferiprone, because of its lower molecular weight, might cross into heart mitochondria more efficiently, improving their activity and, thereby, myocardial cell function. Our findings indicate that the long-term administration of deferiprone significantly enhances left-ventricular function over time in comparison with deferoxamine treatment. However, because of limitations related to the design of this study, these findings should be confirmed in a prospective, randomized clinical trial.

Cardiac and hepatic iron and ejection fraction in thalassemia major: multicentre prospective comparison of combined deferiprone and deferoxamine therapy against deferiprone or deferoxamine monotherapy.

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

Feasibility, reproducibility, and reliability for the T*2 iron evaluation at 3 T in comparison with 1.5 T.

This study aimed to determine the feasibility, reproducibility, and reliability of the multiecho T*(2) Magnetic resonance imaging technique at 3 T for myocardial and liver iron burden quantification and the relationship between T*(2) values at 3 and 1.5 T. Thirty-eight transfusion-dependent patients and 20 healthy subjects were studied. Cardiac segmental and global T*(2) values were calculated after developing a correction map to compensate the artifactual T*(2) variations. The hepatic T*(2) value was determined over a region of interest. The intraoperator and interoperator reproducibility for T*(2) measurements at 3 T was good. A linear relationship was found between patients' R *2 (1000/T*(2) ) values at 3 and 1.5 T. Segmental correction factors were significantly higher at 3 T. A conversion formula returning T*(2) values at 1.5 T from values at 3 T was proposed. A good diagnostic reliability for T*(2) assessment at 3 T was demonstrated. Lower limits of normal for 3 T T*(2) values were 23.3 ms, 21.1 ms, and 11.7 ms, for the global heart, mid-ventricular septum, and liver, respectively. In conclusion, T*(2) quantification of iron burden in the mid-ventricular septum, global heart, and no heavy-moderate livers resulted to be feasible, reproducible, and reliable at 3 T. Segmental heart T*(2) analysis at 3 T may be challenging due to significantly higher susceptibility artifacts.

Long-term use of deferiprone significantly enhances left-ventricular ejection function in thalassemia major patients.

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

The The use of oral glucose-lowering agents (GLAs) in ß-thalassemia patients with diabetes: Preliminary data from a retrospective study of ICET-A Network.

OBJECTIVE: The management of prediabetes and hyperglycemia is an increasingly important aspect of care in patients with thalassemia. In light of the limited evidence about the management of GD (glucose dysregulation) with glucose-lowering agents (GLAs), we have conducted a retrospective survey in TDT and NTDT patients with diabetes mellitus to collect more detailed information on GLA use in order to make preliminary recommendations. STUDY DESIGN AND METHOD: A questionnaire was prepared and distributed to the tertiary thalassemia care Centers of ICET-A Network. RESULTS: Eight  thalassemia care Centers [Bulgaria, Greece, Iran, Italy (4 Centers) and Qatar], following 1.554 with transfusion-dependent thalassemia (TDT), 132 (8.4%) with diabetes and 687 with non-transfusion-dependent thalassemia (NTDT), 27 (3.9%) with diabetes, participated in the retrospective survey. The records of 117 TDT patients and 9 NTDT patients with diabetes treated with GLAs were analyzed. Metformin, a biguanide, was the most frequently used drug (47.6 %), followed by alpha-glucosidase inhibitors (5.5 %), incretins (4.7%) and insulin secretagogues (3.1%).  In 68 (61.2) patients  GLAs was prescribed as monotherapy, while the remaining  49  (38.8%), who had inadequate glucose control with metformin, were treated with combination treatment. Fifty-one patients  of 126 (40.4%) initially treated with oral GLA, for a mean duration of 61.0 ± 35.6 months (range: 12- 120 months), required insulin therapy for better metabolic control. CONCLUSION: This retrospective study covers an unexplored area of research in patients with thalassemia and GD. Oral GLAs appear to be safe and effective for the treatment of diabetes mellitus in patients with thalassemia, and can achieve adequate glycemic control for a substantial period of time.

Transfusional Approach in Multi-Ethnic Sickle Cell Patients: Real-World Practice Data From a Multicenter Survey in Italy.

Sickle cell disease (SCD) is a worldwide distributed hereditary red cell disorder characterized by recurrent acute vaso-occlusive crises (VOCs and anemia). Gold standard treatments are hydroxycarbamide (HC) and/or different red blood cell (RBC) transfusion regimens to limit disease progression. Here, we report a retrospective study on 1,579 SCD patients (median age 23 years; 802 males/777 females), referring to 34 comprehensive Italian centers for hemoglobinopathies. Although we observed a similar proportion of Caucasian (47.9%) and African (48.7%) patients, Italian SCD patients clustered into two distinct overall groups: children of African descent and adults of Caucasian descent. We found a subset of SCD patients requiring more intensive therapy with a combination of HC plus chronic transfusion regimen, due to partial failure of HC treatment alone in preventing or reducing sickle cell-related acute manifestations. Notably, we observed a higher use of acute transfusion approaches for SCD patients of African descent when compared to Caucasian subjects. This might be related to (i) age of starting HC treatment; (ii) patients' low social status; (iii) patients' limited access to family practitioners; or (iv) discrimination. In our cohort, alloimmunization was documented in 135 patients (8.5%) and was more common in Caucasians (10.3%) than in Africans (6.6%). Alloimmunization was similar in male and female and more frequent in adults than in children. Our study reinforces the importance of donor-recipient exact matching for ABO, Rhesus, and Kell antigen systems for RBC compatibility as a winning strategy to avoid or limit alloimmunization events that negatively impact the clinical management of SCD-related severe complications. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT03397017.

Sequential alternating deferiprone and deferoxamine treatment compared to deferiprone monotherapy: main findings and clinical follow-up of a large multicenter randomized clinical trial in -thalassemia major patients.

In ß-thalassemia major (ß-TM) patients, iron chelation therapy is mandatory to reduce iron overload secondary to transfusions. Recommended first line treatment is deferoxamine (DFO) from the age of 2 and second line treatment after the age of 6 is deferiprone (L1). A multicenter randomized open-label trial was designed to assess the effectiveness of long-term alternating sequential L1-DFO vs. L1 alone iron chelation therapy in ß-TM patients. Deferiprone 75 mg/kg 4 days/week and DFO 50 mg/kg/day for 3 days/week was compared with L1 alone 75 mg/kg 7 days/week during a 5-year follow-up. A total of 213 thalassemia patients were randomized and underwent intention-to-treat analysis. Statistically, a decrease of serum ferritin level was significantly higher in alternating sequential L1-DFO patients compared with L1 alone patients (p = 0.005). Kaplan-Meier survival analysis for the two chelation treatments did not show statistically significant differences (log-rank test, p = 0.3145). Adverse events and costs were comparable between the groups. Alternating sequential L1-DFO treatment decreased serum ferritin concentration during a 5-year treatment by comparison to L1 alone, without significant differences of survival, adverse events or costs. These findings were confirmed in a further 21-month follow-up. These data suggest that alternating sequential L1-DFO treatment may be useful for some ß-TM patients who may not be able to receive other forms of chelation treatment.

Paraplegia in a thalassaemic patient with short stature.

Extramedullary hematopoiesis (EMH) is a normal compensatory reaction that occurs in almost all chronic hemolytic anemia, especially in transfusion independent thalassemia intermedia, and can involve many organs or tissues, including the epidural space leading to spinal cord compression syndrome. We present a case of EMH in a 29 year old woman with thalassemia major, regularly transfused since the time of diagnosis (age 21 months), who presented with sudden muscle weakness, difficulty walking and maintaining the upright position. Magnetic Resonance Imaging (MRI) of the thoracic spine showed spinal cord compression secondary to extramedullary hematopoiesis in the spinal canal, leading to early therapy. The neurosurgical treatment (decompressive laminectomy D3-D6) in our patient brought a significant and rapid recovery. The next two MRI of the spine (after 6 and 18 months) were both negative for recurrence.

The Prevalence of glucose dysregulations (GDs) in patients with ß-thalassemias in different countries: A preliminary ICET-A survey.

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Genotypic groups as risk factors for cardiac magnetic resonance abnormalities and complications in thalassemia major: a large, multicentre study.

BACKGROUND: The causes and effects of genotypic heterogeneity in beta-thalassemia major (ß-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 ß-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: ß+ homozygotes (n=158), ß+/ß° heterozygotes (n=298) and ß° homozygotes (n=252). Compared to ß+ 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. ß° homozygotes showed a significantly higher risk than ß+ 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 ß-TM patients. These data support the importance of genotype knowledge in the management of ß-TM patients.