Defining serum ferritin thresholds to predict clinically relevant liver iron concentrations for guiding deferasirox therapy when MRI is unavailable in patients with non‐transfusion‐dependent thalassaemia

Liver iron concentration (LIC) assessment by magnetic resonance imaging (MRI) remains the gold standard to diagnose iron overload and guide iron chelation therapy in patients with non‐transfusion‐dependent thalassaemia (NTDT). However, limited access to MRI technology and expertise worldwide makes it practical to also use serum ferritin assessments. The THALASSA (assessment of Exjade^® in non‐transfusion‐dependent THALASSemiA patients) study assessed the efficacy and safety of deferasirox in iron‐overloaded NTDT patients and provided a large data set to allow exploration of the relationship between LIC and serum ferritin. Using data from screened patients and those treated with deferasirox for up to 2 years, we identified clinically relevant serum ferritin thresholds (for when MRI is unavailable) for the initiation of chelation therapy (>800 μg/l), as well as thresholds to guide chelator dose interruption (<300 μg/l) and dose escalation (>2000 μg/l). (clinicaltrials.gov identifier: NCT00873041).     

Efficacy and safety of deferasirox,an oral iron chelator,in heavily iron-overloaded patients with β-thalassaemia: the ESCALATOR study

Objective: Many patients with transfusional iron overload are at risk for progressive organ dysfunction and early death and poor compliance with older chelation therapies is believed to be a major contributing factor. Phase II/III studies have shown that oral deferasirox 20–30 mg/kg/d reduces iron burden, depending on transfusional iron intake. Methods: The prospective, open-label, 1-yr ESCALATOR study in the Middle East was designed to evaluate once-daily deferasirox in patients ≥2 yr with β-thalassaemia major and iron overload who were previously chelated with deferoxamine and/or deferiprone. Most patients began treatment with deferasirox 20 mg/kg/d; doses were adjusted in response to markers of over- or under-chelation. The primary endpoint was treatment success, defined as a reduction in liver iron concentration (LIC) of ≥3 mg Fe/g dry weight (dw) if baseline LIC was ≥10 mg Fe/g dw, or final LIC of 1–7 mg Fe/g dw for patients with baseline LIC of 2 to <10 mg Fe/g dw. Results: Overall, 233/237 enrolled patients completed 1 yr’s treatment. Mean baseline LIC was 18.0 ± 9.1 mg Fe/g dw, while median serum ferritin was 3356 ng/mL. After 1 yr’s deferasirox treatment, the intent-to-treat population experienced a significant treatment success rate of 57.0% (P = 0.016) and a mean reduction in LIC of 3.4 mg Fe/g dw. Changes in serum ferritin appeared to parallel dose increases at around 24 wk. Most patients (78.1%) underwent dose increases above 20 mg/kg/d, primarily to 30 mg/kg/d. Drug-related adverse events were mostly mild to moderate and resolved without discontinuing treatment. Conclusions: The results of the ESCALATOR study in primarily heavily iron-overloaded patients confirm previous observations in patients with β-thalassaemia, highlighting the importance of timely deferasirox dose adjustments based on serum ferritin levels and transfusional iron intake to ensure patients achieve their therapeutic goal of maintenance or reduction in iron burden.     

Chelation use and iron burden in North American and British thalassemia patients: a report from the Thalassemia Longitudinal Cohort

Morbidity and mortality in thalassemia are associated with iron burden. Recent advances in organ-specific iron imaging and the availability of oral deferasirox are expected to improve clinical care, but the extent of use of these resources and current chelation practices have not been well described. In the present study, we studied chelation use and the change in iron measurements in 327 subjects with transfusion-dependent thalassemia (mean entry age, 22.1 ± 2.5 years) from 2002-2011, with a mean follow-up of 8.0 years (range, 4.4-9.0 years). The predominant chelator currently used is deferasirox, followed by deferoxamine and then combination therapies. The use of both hepatic and cardiac magnetic resonance imaging increased more than 5-fold (P < .001) during the study period, leading to an 80% increase in the number of subjects undergoing liver iron concentration (LIC) measurements. Overall, LIC significantly improved (median, 10.7 to 5.1 mg/g dry weight, P < .001) with a nonsignificant improvement in cardiac T2* (median, 23.55 to 34.50 ms, P = .23). The percentage of patients with markers of inadequate chelation (ferritin > 2500 ng/mL, LIC > 15 mg/g dry weight, and/or cardiac T2* < 10 ms) also declined from 33% to 26%. In summary, increasing use of magnetic resonance imaging and oral chelation in thalassemia management has likely contributed to improved iron burden.     

Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-yr prospective study

Objectives/methods:  This 1-yr prospective phase II trial evaluated the efficacy of deferasirox in regularly transfused patients aged 3–81 yrs with myelodysplastic syndromes (MDS; n  = 47), Diamond–Blackfan anaemia (DBA; n  = 30), other rare anaemias ( n  = 22) or β-thalassaemia ( n  = 85). Dosage was determined by baseline liver iron concentration (LIC).
Results:  In patients with baseline LIC ≥7 mg Fe/g dry weight, deferasirox initiated at 20 or 30 mg/kg/d produced statistically significant decreases in LIC ( P  < 0.001); these decreases were greatest in MDS and least in DBA. As chelation efficiency and iron excretion did not differ significantly between disease groups, the differences in LIC changes are consistent with mean transfusional iron intake (least in MDS: 0.28 ± 0.14 mg/kg/d; greatest in DBA: 0.4 ± 0.11 mg/kg/d). Overall, LIC changes were dependent on dose ( P  < 0.001) and transfusional iron intake ( P  < 0.01), but not statistically different between disease groups. Changes in serum ferritin and LIC were correlated irrespective of disease group ( r  = 0.59), supporting the potential use of serum ferritin for monitoring deferasirox therapy. Deferasirox had a safety profile compatible with long-term use. There were no disease-specific safety/tolerability effects: the most common adverse events were gastrointestinal disturbances, skin rash and non-progressive serum creatinine increases.
Conclusions:  Deferasirox is effective for reducing iron burden with a defined, clinically manageable safety profile in patients with various transfusion-dependent anaemias. There were no disease-specific adverse events. Once differences in transfusional iron intake are accounted for, dose-dependent changes in LIC or serum ferritin are similar in MDS and other disease groups.     

Observational study comparing long-term safety and efficacy of Deferasirox with Desferrioxamine therapy in chelation-naïve children with transfusional iron overload

Objectives: An observational study was conducted to explore postmarketing safety and efficacy of Deferasirox (DFX) in comparison with conventional Desferrioxamine (DFO) in chelation‐naïve children with transfusional iron overload. Methods: Transfusion‐dependent children (aged ≤5 yr) who had serum ferritin above 1000 μg/L and had been prescribed either first‐line DFX or DFO for at least 12 months to maintain serum ferritin between 500 and 1000 μg/L were included. Initial DFX dose was 20 mg/kg/d for 7 d a week, and DFO dose was 25–35 mg/kg/d subcutaneously, given for 5 d a week. Dose adjustments were based on serum ferritin changes and safety markers. The primary efficacy endpoint was change in serum ferritin from baseline. The effect of transfusional iron loading rate (ILR) and different doses of chelators on serum ferritin was also assessed. Results: A total of 111 patients were observed for a median of 2.29 yr on DFX (n = 71) and 2.75 yr on DFO (n = 40). Absolute change in serum ferritin from baseline to the last available observation was not significant with DFX (91 μg/L, P = 0.5) but significantly higher with DFO (385 μg/L, P < 0.005). ILR and DFX doses had a major impact on serum ferritin changes in DFX cohort. The height‐ and weight‐standard deviation scores did not differ significantly in both cohorts during the study. Fluctuations in liver enzymes and non‐progressive increase in serum creatinine were the most common adverse events (DFX; 9.8%, 18.0% and DFO; 5.0%, 7.5%, respectively). Conclusion: DFX is well tolerable and at least as effective as DFO to maintain safe serum ferritin levels and normal growth progression in chelation‐naïve children.     

A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia

Deferasirox (ICL670) is a once-daily oral iron chelator developed for the treatment of chronic iron overload from blood transfusions. A comparative phase 3 trial was conducted to demonstrate the efficacy of deferasirox in regularly transfused patients with beta-thalassemia aged 2 years or older. Patients were randomized and received treatment with deferasirox (n = 296) or deferoxamine (n = 290), with dosing of each according to baseline liver iron concentration (LIC). The primary endpoint was maintenance or reduction of LIC; secondary endpoints included safety and tolerability, change in serum ferritin level, and net body iron balance. In both arms, patients with LIC values of 7 mg Fe/g dry weight (dw) or higher had significant and similar dose-dependent reductions in LIC and serum ferritin, and effects on net body iron balance. However, the primary endpoint was not met in the overall population, possibly due to the fact that proportionally lower doses of deferasirox relative to deferoxamine were administered to patients with LIC values less than 7 mg Fe/g dw. The most common adverse events included rash, gastrointestinal disturbances, and mild nonprogressive increases in serum creatinine. No agranulocytosis, arthropathy, or growth failure was associated with deferasirox administration. Deferasirox is a promising once-daily oral therapy for the treatment of transfusional iron overload.     

Deferasirox for iron chelation in multitransfused children with sickle cell disease; long‐term experience in the East London clinical haemoglobinopathy network

Deferasirox (DFX) has been licensed for iron chelation in patients with sickle cell disease (SCD), but there is limited data on its long‐term efficacy and safety in children. This retrospective study included 62 regularly transfused children managed in the East London and Essex Clinical Haemoglobinopathy Network (mean age 9.2 ± 3.2 yr). Efficacy measurements consisted of monthly serum ferritin (SF) and annual R2 MRI‐estimated liver iron concentration (LIC), and safety markers included serum creatinine and alanine aminotransferase (ALT). The mean duration of DFX treatment was 2.5 ± 1.4 yr, and mean dose at 36 months was 25 mg/kg/d. Mean SF at initiation of treatment was 2542 ± 952 ng/mL and increased to 4691 ± 2255 ng/mL at 36 months (P = 0.05). Mean LIC on first scan was 10.3 mg/g dry weight and did not decrease significantly on follow‐up scans. There was a significant correlation between relative change in LIC and in SF (R² = 0.66, P < 0.001). Reversible transaminitis episodes, probably due to drug‐induced hepatitis, were noted in 53% of patients. Responses to an adherence and acceptability questionnaire indicated that more than 50% of children had difficulties in taking DFX, commonly because of unpleasant taste. Our results show that more than 50% of children with SCD have inadequate control of iron overload with DFX. It is not clear whether this is because of frequent dose interruptions, poor tolerability and adherence, or poor efficacy of the drug. We recommend further studies to confirm these findings and to optimise iron chelation in this population.     

Absence of cardiac siderosis by MRI T2* despite transfusion burden,hepatic and serum iron overload in Lebanese patients with sickle cell disease

Background: The use of magnetic resonance imaging (MRI) to detect organ‐specific iron overload is becoming increasingly common. Although hepatic iron overload has been recognized in patients with sickle cell disease (SCD), cardiac iron deposition has only been examined in a few reports. Methods: This was a cross‐sectional study of 23 patients with SCD. Patient charts were reviewed and data collected for drug use, total lifetime transfusions (TLT), transfusion rate (TR), status of the spleen, and comorbid illnesses or infections. Blood samples were obtained for assessment of hemoglobin, serum ferritin, non‐transferrin‐bound iron (NTBI), and liver enzyme levels. Doppler echocardiography was performed to detect pulmonary hypertension (PHT) and assess left ventricular ejection fraction. Cardiac iron levels were measured by MRI T2*. Direct determination of liver iron concentration (LIC) was performed using R2 MRI. In this study, cardiac T2* >20 ms was considered normal. Results: The mean age was 24.4 ± 9.7 yr, with a male to female ratio of 15:8. A total of 9 (49.9%) patients were splenectomized. The mean TR was 14.1 ± 13.2 Units/yr, and the mean hemoglobin level was 9.0 g/dL. PHT was detected in 6 (27.3%) patients, but none had evidence of heart failure. The mean serum ferritin, LIC, and NTBI levels were 997.7 ng/mL, 4.6 mg Fe/g dw, and 1.1 ± 2.2, respectively. TR was a much better predictor of iron burden (LIC, ferritin, NTBI) than TLT. In fact, TR less than 10 Units/yr did not produce significant iron overload reflecting spontaneous losses as high as 0.11 mg/kg/d. None of the patients had evidence of cardiac iron overload (mean cardiac T2* = 37.3 ± 6.2 ms; range: 21.9–46.8 ms). There was also no statistically significant correlation between cardiac T2* values and any of the study variables. Conclusion: Our study demonstrates that TR is a stronger predictor of iron overload than TLT. It also confirms cardiac sparing in patients with SCD, even in subjects with significant transfusion burden, systemic and hepatic iron overload.     

Liver complications of haemoglobin H disease in adults

Haemoglobin H (HbH) disease is a type of non‐transfusion‐dependent thalassaemia. This cross‐sectional study aimed at determining the prevalence and severity of liver iron overload and liver fibrosis in patients with HbH disease. Risk factors for advanced liver fibrosis were also identified. A total of 80 patients were evaluated [median (range) age 53 (24–79) years, male 34%, non‐deletional HbH disease 24%]. Patients underwent ‘observed’ T2‐weighted magnetic resonance imaging examination for liver iron concentration (LIC) quantification, and transient elastography for liver stiffness measurement (LSM) and fibrosis staging. In all, 25 patients (31%) had moderate‐to‐severe liver iron overload (LIC ≥7 mg/g dry weight). The median LIC was higher in non‐deletional than in deletional HbH disease (7·8 vs. 2.9 mg/g dry weight, P = 0·002). In all, 16 patients (20%) had advanced liver fibrosis (LSM >7.9 kPa) and seven (9%) out of them had probable cirrhosis (LSM >11.9 kPa). LSM positively correlated with age (R = 0·24, P = 0·03), serum ferritin (R = 0·36, P = 0·001) and LIC (R = 0·28, P = 0·01). In multivariable regression, age ≥65 years [odds ratio (OR) 4·97, 95% confidence interval (CI) 1·52–17·50; P = 0·047] and moderate‐to‐severe liver iron overload (OR 3·47, 95% CI 1·01–12·14; P = 0·01) were independently associated with advanced liver fibrosis. The findings suggest that regular screening for liver complications should be considered in the management of HbH disease.     

Achieving treatment goals of reducing or maintaining body iron burden with deferasirox in patients with β-thalassaemia: results from the ESCALATOR study

This analysis evaluated the effects of deferasirox on liver iron concentration in moderate and heavily iron-overloaded patients with β-thalassaemia from the ESCALATOR trial (n = 231). Mean liver iron concentrations (LIC) decreased significantly from 21.1 ± 8.2 to 14.2 ± 12.1 mg Fe/g dry weight (dw) at 2 yr (P < 0.001) in patients with LIC ≥ 7 mg Fe/g dw at baseline; patients with LIC < 7 mg Fe/g dw maintained these levels over the treatment period. The proportion of patients with LIC < 7 mg Fe/g dw increased from 9.4% at core baseline to 39.3% by the end of year 2. The results showed that deferasirox enabled therapeutic goals to be achieved, by maintaining LIC in patients with LIC < 7 mg Fe/g dw at a mean dose of 22.4 ± 5.2 mg/kg/d and significantly reducing LIC in patients with LIC ≥ 7 mg Fe/g dw at a mean dose of 25.7 ± 4.2 mg/kg/d, along with a manageable safety profile.     

Deferasirox treatment of iron-overloaded chelation-naïve and prechelated patients with myelodysplastic syndromes in medical practice: results from the observational studies eXtend and eXjange

EXtend and eXjange were prospective, 1‐yr, non‐interventional, observational, multicentre studies that investigated deferasirox, a once‐daily oral iron chelator, in iron‐overloaded chelation‐naïve and prechelated patients with myelodysplastic syndromes (MDS), respectively, treated in the daily‐routine setting of office‐based physicians. No inclusion or exclusion criteria or additional monitoring procedures were applied. Deferasirox was administered as recommended in the European Summary of Product Characteristics. Haematological parameters and adverse events (AEs) were collected at two‐monthly intervals. Data from 123 chelation‐naïve patients with MDS (mean age 70.4 yrs) with median baseline serum ferritin level of 2679 (range 184–16 500) ng/mL, and 44 prechelated patients with MDS (mean age 69.6 yrs) with median baseline serum ferritin level of 2442 (range 521–8565) ng/mL, were assessed. The mean prescribed daily dose of deferasirox at the first visit was 15.7 and 18.7 mg/kg/d, respectively. Treatment with deferasirox produced a significant reduction in median serum ferritin levels in chelation‐naïve patients with MDS from 2679 to 2000 ng/mL (P = 0.0002) and a pronounced decrease in prechelated patients with MDS from 2442 to 2077 ng/mL (P = 0.06). The most common drug‐related AEs were gastrointestinal, increased serum creatinine levels and rash. These studies demonstrate that deferasirox used in physicians’ medical practices is effective in managing iron burden in transfusion‐dependent patients with MDS.     

Iron overload in congenital haemolytic anaemias: role of hepcidin and cytokines and predictive value of ferritin and transferrin saturation

Iron overload (IO) is poorly investigated in the congenital haemolytic anaemias (CHAs), a heterogeneous group of rare inherited diseases encompassing abnormalities of the erythrocyte membrane and metabolism, and defects of the erythropoiesis. In this study we systematically evaluated routine iron parameters and cardiac and hepatic magnetic resonance imaging, together with erythropoietin, hepcidin, non-transferrin bound iron (NTBI), and cytokine serum levels in patients with different CHAs. We found that 40% of patients had a liver iron concentration (LIC) >4 mg Fe/g dry weight. Hepatic IO was associated with ferritin levels (P = 0·0025), transferrin saturation (TfSat, P = 0·002) and NTBI (P = 0·003). Moreover, ferritin >500 μg/l plus TfSat >60% was demonstrated as the best combination able to identify increased LIC, and TfSat alteration as more important in cases with discordant values. Possible confounding factors, such as transfusions, hepatic disease, metabolic syndrome and hereditary haemochromatosis-associated mutations, had negligible effects on IO. Erythropoietin and hepcidin levels were increased in CHAs compared with controls, correlating with LIC and ferritin, respectively. Regarding cytokines, γ-interferon (IFN-γ) was increased, and both interleukin 6 and IFN-γ levels positively correlated with ferritin and hepcidin levels. Overall, these findings suggest the existence of a vicious cycle between chronic haemolysis, inflammatory response and IO in CHAs.     

Ferritin trends do not predict changes in total body iron in patients with transfusional iron overload

Ferritin levels and trends are widely used to manage iron overload and assess the efficacy of prescribed iron chelation in patients with transfusional iron loading. A retrospective cohort study was conducted in 134 patients with transfusion‐dependent anemia, over a period of up to 9 years. To determine whether the trends in ferritin adequately reflect the changes in total body iron, changes in ferritin between consecutive liver iron measurements by magnetic resonance imaging (MRI) were compared to changes in liver iron concentrations (LIC), a measure of total body iron. The time period between two consecutive LIC measurements was defined as a segment. Trends in ferritin were considered to predict the change in LIC within a segment if the change in one parameter was less than twofold that of the other, and was in the same direction. Using the exclusion criteria detailed in methods, the trends in ferritin were compared to changes in LIC in 358 segments. An agreement between ferritin trends and LIC changes was found in only 38% of the 358 segments examined. Furthermore, the change in ferritin was in opposite direction to that of LIC in 26% of the segments. Trends in ferritin were a worse predictor of changes in LIC in sickle cell disease than in thalassemia (P < 0.01). While ferritin is a convenient measure of iron status; ferritin trends were unable to predict changes in LIC in individual patients. Ferritin trends need to be interpreted with caution and confirmed by direct measurement of LIC. Am. J. Hematol. 89:391–394, 2014. © 2013 Wiley Periodicals, Inc.     

Combined chelation therapy in thalassemia major with deferiprone and desferrioxamine: a retrospective study

Objectives: The benefits of combined chelation therapy with daily deferiprone (DFP) and subcutaneous desferrioxamine (DFO) have been widely reported in literature. We retrospectively evaluated the efficacy of different schedules of combined chelation therapy and the incidence of adverse events. Methods: We evaluated 36 patients affected by thalassemia major treated with combined chelation therapy. Patients were subdivided into four treatment arms according to severity of iron overload and previous onset of adverse events to DFP therapy: Group 1 (13 pts) DFP 75 mg/kg per d plus DFO (25–35 mg/kg per d for 5 d); Group 2 (6 pts) DFP 50 mg/kg per d plus DFO (25–35 mg/kg for 5 d), Group 3 (10 pts) DFP 75 mg/kg per d plus DFO (25–35 mg/kg for 3 d), and Group 4 (7 pts) DFP 50 mg/kg per d plus DFO (25–35 mg/kg for 3 d). Change in serum ferritin level was evaluated in all patients. Results: Overall, ferritin decreased from 2592 ± 1701 to 899 ± 833 ng/mL (P < 0.001). All treatments were able to reduce ferritin levels, but in patients of group 1 and group 2 the highest mean decrease in serum ferritin level and the greatest improvement in liver iron concentration (LIC) and in T2* values were observed. Conclusions: This study showed that the administration of DFO for 5 d a wk in combination with daily administration of DFP at 75 mg/Kg seemed to be the most efficacy and rapid method for reducing iron overload at liver and heart level. Furthermore, the use of different schedules of combined DFO and DFP administration was not associated with different incidence of adverse effects between the groups.     

Labile plasma iron,more practical and more sensitive to iron overload in myelodysplastic syndromes

Objectives: In order to gain an insight into labile plasma iron (LPI) in iron metabolism microenvironment in MDS.

Methods: We performed ELISA, quantitative real-time polymerase chain reaction, flow cytometry, MRI T2* assays to test LPI, iron biochemical parameters, and liver iron concentration (LIC) among 22 MDS patients.

Results: LPI has a statistical difference (P?P?=?0.086 by ANOVA). After DFO treatment, serum hepcidin expression increased from 301.26?±?59.78 to 340.33?±?49.78?µg/l (P?=?0.032), while hepcidin/ASF was upregulated gradually from 0.16?±?0.08 to 0.22?±?0.03 (P?=?0.045). APAF-1 expression (P?=?0.047) and erythroid apoptosis rate (P?=?0.009) decreased significantly, respectively. No statistical difference was found in EPO (P?=?0.247) and GDF15 expression (P?=?0.172). LIC dropped from 9.83?±?4.84 to 6.28?±?4.01?mg/g dry weight (P?P?=?0.594). LPI has a closer connection to LIC than ASF (r?=?0.739, P?r?=?0.321, P?=?0.034).

Discussion: LPI seems to be a real-time indicator which reflects body iron loading status instantaneously. Despite the limited knowledge available on LPI speciation in different types and degrees of IO, LPI measurements can be and are in fact used for identifying systemic IO and for initiating/adjusting chelation regimens.     

MRI guided iron assessment and oral chelator use improve iron status in thalassemia major patients

Oral iron chelators and magnetic resonance imaging (MRI) assessment of heart and liver iron burden have become widely available since the mid 2000s, allowing for improved patient compliance with chelation and noninvasive monitoring of iron levels for titration of therapy. We evaluated the impact of these changes in our center for patients with thalassemia major and transfusional iron overload. This single center, retrospective observational study covered the period from 2005 through 2012. Liver iron content (LIC) was estimated both by a T2* method and by R2 (Ferriscan^®) technique. Cardiac iron was assessed as cT2*. Forty‐two patients (55% male) with transfused thalassemia and at least two MRIs were included (median age at first MRI, 17.5 y). Over a mean follow‐up period of 5.2 ± 1.9 y, 190 MRIs were performed (median 4.5 per patient). Comparing baseline to last MRI, 63% of patients remained within target ranges for cT2* and LIC, and 13% improved from high values to the target range. Both the median LIC and cT2* (cR2* = 1000/cT2*) status improved over time: LIC 7.3 to 4.5 mg/g dry weight, P = 0.0004; cR2* 33.4 to 28.3 Hz, P = 0.01. Individual responses varied widely. Two patients died of heart failure during the study period. Annual MRI iron assessments and availability of oral chelators both facilitate changes in chelation dose and strategies to optimize care. Am. J. Hematol. 89:684–688, 2014. © 2014 Wiley Periodicals, Inc.     

Deferasirox effectively reduces iron overload in non-transfusion-dependent thalassemia (NTDT) patients: 1-year extension results from the THALASSA study

Patients with non-transfusion-dependent thalassemia (NTDT) often develop iron overload that requires chelation to levels below the threshold associated with complications. This can take several years in patients with high iron burden, highlighting the value of long-term chelation data. Here, we report the 1-year extension of the THALASSA trial assessing deferasirox in NTDT; patients continued with deferasirox or crossed from placebo to deferasirox. Of 133 patients entering extension, 130 completed. Liver iron concentration (LIC) continued to decrease with deferasirox over 2 years; mean change was ?7.14 mg Fe/g dry weight (dw) (mean dose 9.8?±?3.6 mg/kg/day). In patients originally randomized to placebo, whose LIC had increased by the end of the core study, LIC decreased in the extension with deferasirox with a mean change of ?6.66 mg Fe/g dw (baseline to month 24; mean dose in extension 13.7?±?4.6 mg/kg/day). Of 166 patients enrolled, 64 (38.6 %) and 24 (14.5 %) patients achieved LIC <5 and <3 mg Fe/g dw by the end of the study, respectively. Mean LIC reduction was greatest in patients with the highest pretreatment LIC. Deferasirox progressively decreases iron overload over 2 years in NTDT patients with both low and high LIC. Safety profile of deferasirox over 2 years was consistent with that in the core study.     

Evaluation of cardiac and hepatic iron overload in thalassemia major patients with T2* magnetic resonance imaging

Objectives: Recent advancements have promoted the use of T2* magnetic resonance imaging (MRI) in the non-invasive detection of iron overload in various organs for thalassemia major patients. This study aims to determine the iron load in the heart and liver of patients with thalassemia major using T2* MRI and to evaluate its correlation with serum ferritin level and iron chelation therapy.

Methods: This cross-sectional study included 162 subjects diagnosed with thalassemia major, who were classified into acceptable, mild, moderate, or severe cardiac and hepatic iron overload following their T2* MRI results, respectively, and these were correlated to their serum ferritin levels and iron chelation therapy.

Results: The study found that 85.2% of the subjects had normal cardiac iron stores. In contrast, 70.4% of the subjects had severe liver iron overload. A significant but weak correlation (r?=??0.28) was found between cardiac T2* MRI and serum ferritin, and a slightly more significant correlation (r?=?0.37) was found between liver iron concentration (LIC) and serum ferritin.

Discussion: The findings of this study are consistent with several other studies, which show that patients generally manifest with liver iron overload prior to cardiac iron overload. Moreover, iron accumulation demonstrated by T2* MRI results also show a significant correlation to serum ferritin levels.

Conclusion: This is the first study of its kind conducted in Indonesia, which supports the fact that T2* MRI is undoubtedly valuable in the early detection of cardiac and hepatic iron overload in thalassemia major patients.     

Magnetic resonance screening of iron status in transfusion-dependent beta-thalassaemia patients

The clinical utility of dual sequence (T1- and T2-weighted) magnetic resonance (MR) imaging in estimating liver iron concentration (LIC) in 32 transfusion-dependent beta-thalassaemia major (24 females; age 18.5+/-5.9 years) patients on desferrioxamine was evaluated. Signal intensity ratios (SIR) between liver, spleen and pancreas to psoas muscle were determined on both sequences. Relationships between clinical and MR parameters, and accuracy of SIR thresholds in determining adequacy of chelation from LIC were analysed. Liver T1- and T2-SIR were related to LIC (P < 0.001). T1-SIR < 0.60 predicted severe iron overload (LIC > 15 mg/g) with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 100%, 87%, 33% and 100% respectively. T2-SIR < 0.1 yielded 100% sensitivity, 93% specificity, 50% PPV and 100% NPV. T1-SIR > or = 1.1 predicted LIC < 7 mg/g with 69% sensitivity, 88% specificity, 85% PPV and 74% NPV. T2-SIR > or = 0.20 yielded 56.5% sensitivity, 94% specificity, 90% PPV and 71% NPV. LIC correlated with liver T1-SIR, liver T2-SIR and serum ferritin (r = -0.76, -0.65, 0.47, respectively; P < 0.01). Serum ferritin was inversely related to liver T1-SIR, liver T2-SIR and spleen T2-SIR (r = -0.35, -0.43, -0.40, respectively; P < 0.05). Mean total transfusion burden was not related to any MR parameter. Although neither MR sequence was a highly accurate predictor of LIC, SIR thresholds are useful to determine presence of iron overload and adequacy of chelation treatment.     

Observational study of iron overload as assessed by magnetic resonance imaging in an adult population of transfusion‐dependent patients with β thalassaemia: significant association between low cardiac T2* < 10 ms and cardiac events

Background: Thalassaemia major patients usually die from cardiac haemosiderosis. Improved strategies are required to modify this risk. Aims: To assess the significance of cardiac iron overload in patients with β thalassaemia. Method: Observational study of cardiac iron overload as assessed by magnetic resonance imaging (MRI) cardiac T2* relaxometry in 30 adult patients with transfusion‐dependent β thalassaemia. Results: 11/30 patients (37%) had cardiac T2* < 10 ms, 8/30 (27%) in range 10–20 ms and 11/30 (37%) > 20 ms. There was significant inverse correlation between T2* values and values for serum ferritin (SF) and liver iron concentration (LIC) and positive correlation with left ventricular ejection fraction (LVEF). Median LVEF values were 49% in patients with T2* < 10 ms and 58% in patients with T2* > 10 ms (P= 0.02). Very low T2* values <10 ms were strongly associated with the occurrence of cardiac events (congestive heart failure, arrhythmia, cardiac death): occurring in 5/11 patients with T2* < l0 ms and in 0/19 in patients with T2* > 10 ms (P= 0.003 Fisher's exact test; P= 0.002 log rank Kaplan‐Meier time to event analysis). There was no significant association between T2* < 10 ms or cardiac events and traditional measures of iron overload, such as SF levels >2500 µg/L and LIC (evaluated at thresholds of >7 or >15 mg/g dry weight). Conclusion: Very low cardiac T2* values <10 ms are common in adults with β thalassaemia and are significantly associated with risk of cardiac events. This permits the use of individually targeted chelation strategies which are more effective in removing cardiac iron.