Introduction
Thalassemia syndromes are inherited hemoglobin disorders resulting from mutations that affect the synthesis of hemoglobin chains. Among these, β-thalassemia is the most prevalent and clinically significant, characterized by reduced or absent production of the β-globin chain of hemoglobin. This condition is particularly common in regions such as the Mediterranean, Middle East, and Southeast Asia. With an estimated 60,000 new cases worldwide each year, β-thalassemia represents a significant global health burden. 1, 2 The disease spectrum of thalassemia varies widely, from asymptomatic carriers to severe transfusion-dependent forms. Transfusion-dependent thalassemia (TDT), primarily consisting of β-thalassemia major, necessitates regular blood transfusions to sustain life. However, the chronic transfusions lead to iron overload, which can cause severe complications, including cardiac, hepatic, and endocrine dysfunction. 3 TDT (Transfusion-Dependent Thalassemia) Patients require regular blood transfusions, Due to frequent transfusions, iron overload occurs rapidly, Leading to Clinical Complications like Pituitary Dysfunction which Leads to endocrine issues such as hypothyroidism and hypoparathyroidism, Cardiac Siderosis due to Iron deposition in the heart, causing arrhythmias and heart failure, Liver Iron overload can lead to liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), Diabetes can occur from pancreatic iron overload, Hypogonadism due to iron deposition in the gonads leading to Impaired sexual development, Bone Disease Associated with poor bone health and development as seen in Figure 1. 4 Transfusion therapy can correct the anemia, which is the cause of death in TDT patients during the first decade of life, and significantly prolong survival 3 However, repeated blood transfusions lead to iron overload, as iron that is not saturated by transferrin becomes a toxic agent. The inability to remove excess iron exposes TDT patients to its toxic effects, leading to death from iron-induced cardiomyopathy in the second decade of life. 5. The availability of non-invasive methods to monitor iron loading and unloading in the liver, heart, and pancreas has significantly increased the survival of patients with thalassemia. 6 Magnetic resonance imaging (MRI), which can accurately monitor multi-organ iron overload (IOL), has enabled a better understanding of the effects of iron chelation therapy. The aim of chelation is to consistently neutralize the toxic effects of iron and prevent or eradicate IOL. This case-based review studies the role of iron chelation therapy (ICT) in the management of iron overload in transfusion-dependent thalassemia patients with currently available iron chelators. 7, 8
Aim and Objective
To study the role of iron chelators in management of iron over load in blood transfusion dependent thalassemia paediatric patients
Materials and Methods
Study location
Study will be conducted in paediatrics department government medical college & government general hospital Ongole for a duration of 12 months.
Study design
It was a descriptive observational study on Children below the age of 12 years who present with haemoglobin levels less than 10 mg/dl are further evaluated using haemoglobin variant analysis by Haemoglobin Electrophoresis High-Performance Liquid Chromatography (HPLC) and patients of transfusion dependent thalassemia are identified. They are given blood transfusion and some develop iron overload, which is evaluated by serum ferritin levels which are high. Those with elevated serum ferritin levels of more than 2000mcg/l are administered iron chelators like Deferasirox (14mg/kg/d). and patients are evaluated for myocardial, hepatic, pancreatic iron burden and conditions of iron toxicity
Ethical approval
Study got clearance from institutional ethics committee, government medical college Ongole. Informed consent from the parents who are willing to participate in the study was obtained.
Pre-treatment assessment
Detailed history and examination of all the systems was done and patients were evaluated for Hemoglobin, Serum ferritin, Transferrin saturation, Transaminases, Serum total bilirubin, Direct bilirubin, Creatinine, Blood Urea, Cardiac MRI T2, LIC (Liver Iron Concentration), MRI T2 Pancreas, LVEF (Left Ventricular Ejection Fraction).
Follow-up
patients were evaluated with following investigations at baseline and on each visit at the end of 6th month and 12th month: Hemoglobin, Serum ferritin, Transferrin saturation, Transaminases, Serum total bilirubin, Direct bilirubin, Creatinine, Blood Urea, Cardiac MRI T2, LIC (Liver Iron Concentration), MRI T2 Pancreas, LVEF (Left Ventricular Ejection Fraction)
Results
22 children satisfying inclusion criteria were enrolled in study baseline Characteristics of patient with transfusion-dependent β-thalassemia major with severe multiorgan iron overload is given in Table 1.
Table 1
Shows baseline characteristics of transfusion dependent beta-thalassemia paediatric patients for evaluating the efficacy of Deferasirox (iron chelation therapy)
Mean serum ferritin in 0 visit was 2388 mcg/dl. Mean Cardiac MRI T2* was 19.55ms, indicating severe IOL with normal left ventricular ejection fraction. Mean liver iron concentration (LIC) was 20.73 mgFe/g dry weight (dw) tissue, and mean pancreatic T2 54.32 ms, Iron chelation was prescribed with oral Deferasirox (DFX) at 14 mg/kg During the 12 months of chelation therapy.
Table 2
Shows baseline characteristics of transfusion dependent beta-thalassemia paediatric patients for assessing the safety of Deferasirox (iron chelation therapy)
Serum ferritin levels
A significant reduction in mean serum ferritin levels was observed from 2388 mcg/dl at baseline to 2054 mcg/dl at 6 months (p=0.0009) as shown in Figure 2. This reduction underscores the effectiveness of Deferasirox (DFX) in mobilizing and reducing iron stores, which is crucial in minimizing the risk of complications such as hepatic and cardiac dysfunction.
Transferrin saturation and serum transaminases
Transferrin saturation
There was a significant decrease from 70.45% to 64.32% (p=0.00005) by the 6th month. This reduction suggests a decrease in iron availability for tissue uptake, reflecting the efficacy of DFX in reducing iron toxicity.
Serum transaminases
A significant reduction was noted from 44.55 U/L to 40.27 U/L at 6 months (p=0.003), indicating improved liver function and reduced hepatic inflammation.
Cardiac MRI T2*
A significant increase in mean cardiac MRI T2* was observed from 19.55 ms to 22.95 ms at 6 months (p=0.0016), and further to 28.23 ms at 12 months (p=0.045) as shown in Figure 3. This improvement indicates a reduction in myocardial iron content, which is critical given the high risk of cardiac complications in thalassemia patients. The maintenance of normal left ventricular ejection fraction throughout the study highlights the cardioprotective effects of DFX.
Liver iron concentration (LIC)
A significant reduction in LIC from 20.73 mg Fe/g dw to 11.59 mg Fe/g dw at 6 months (p=0.00005) was observed as shown in Figure 4, demonstrating the efficacy of DFX in reducing hepatic iron burden. This is crucial in preventing liver-related complications such as fibrosis and cirrhosis.
Pancreatic MRI T2*
The mean pancreatic T2* significantly increased from 15.96 ms at baseline to 20.23 ms at 12 months (p=0.007) as shown in Figure 5. This suggests a reduction in pancreatic iron deposition, potentially lowering the risk of developing diabetes mellitus, a common complication in thalassemia.
Table 3
Shows mean values of each parameter at each visit for evaluating the efficacy of Deferasirox therapy in transfusion-dependent beta-thalassemia paediatric patients
Total and direct bilirubin
Total bilirubin
Although a slight increase in mean total bilirubin from 1.05 mg/dl to 1.16 mg/dl was observed at 6 months, this change was not clinically significant. However, by 12 months, a significant reduction to 0.54 mg/dl was noted (p=0.000019), indicating an overall improvement in hepatic function.
Direct bilirubin
A modest yet significant reduction from 0.46 mg/dl to 0.45 mg/dl (p=0.029) further supports improved liver function.
Table 4
Shows mean values of each parameter at each visit for evaluating the safety of Deferasirox therapy in transfusion-dependent beta-thalassemia paediatric patients
Safety and tolerability
There was an increase in mean serum creatinine from 0.64+/-0.14 mg/dL to 0.7+/-0.13 mg/dL was seen at the end of 6 months of treatment with Deferasirox (14 mg/kg) which was statistically significant (P=0.009), but the values of serum creatinine returned to normal at the end of 12 months to 0.63 mg/dL.
Discussion
The results of this study underscore the efficacy of Deferasirox (DFX) in managing iron overload in paediatric patients with transfusion-dependent beta-thalassemia. Over a 12-month period, significant improvements were observed in several critical parameter’s indicative of iron burden and organ function, suggesting that DFX is a potent therapeutic agent in this context. Our findings are consistent with and extend the body of literature on the management of iron overload in beta-thalassemia.
Serum ferritin levels
The mean serum ferritin levels in our study significantly decreased from 2388 mcg/dl at the initial visit to 2054 mcg/dl at the end of 6 months (p=0.0009). This reduction aligns with the findings of Taher et al where serum ferritin reduced significantly from 4,139 ng/mL at baseline to 3,176 ng/mL at 12 months 9, who reported similar decreases in serum ferritin with Deferasirox therapy in a multicenter study. Another study by Cappellini et al demonstrated that DFX effectively lowers serum ferritin levels in both pediatric and adult populations where mean serum ferritin levels reduced from 3148 mcg/dl to 1626 mcg/dl Over the course of the 5-year. 10 This reduction is crucial as elevated ferritin levels are associated with increased morbidity and mortality due to iron overload-related complications.
Transferrin saturation and serum transaminases
The significant reduction in transferrin saturation from 70.45% to 64.32% (p=0.00005) and serum transaminases from 44.55 U/L to 40.27 U/L (p=0.003) at 6 months indicates improved iron metabolism and reduced hepatic inflammation, respectively. This aligns with studies by Porter et al. and Galanello et al., which reported that DFX therapy effectively lowers transferrin saturation and improves liver function, reducing hepatic stress and potential damage. 11, 12
Cardiac MRI T2*
The mean cardiac MRI T2* increased from 19.55 ms to 22.95 ms (p=0.045) over the first 6 months, indicating a reduction in myocardial iron content. This improvement is particularly significant as cardiac complications are a leading cause of mortality in thalassemia patients. Our findings are similar to study conducted by Pennell et al where After 1 year of treatment with deferosirox 17.6% patients normalized their myocardial T2*, and 35.5% patients improved myocardial T2* from a baseline of 6 to <10 milliseconds to 10 to ≤20 milliseconds. 2 The maintenance of normal left ventricular ejection fraction throughout our study further supports the cardioprotective effect of DFX, as seen in other studies.
Liver Iron Concentration (LIC)
Our study showed a significant reduction in LIC from 20.73 mg Fe/g dw to 11.59 mg Fe/g dw at the end of 6 months (p=0.00005). Comparable reductions in LIC have been reported by Voskaridou et al where the mean LIC reduced significantly from 31.2 mg Fe/g dw to 24.2 mg Fe/g dw after 12 months of deferasirox therapy and El-Beshlawy et al where significant reduction in LIC from 15.4 mg Fe/g dw to 11.5 mg Fe/g dw over 12 months with deferasirox treatment (15), who demonstrated that DFX is effective in decreasing hepatic iron burden, thereby reducing the risk of liver fibrosis and cirrhosis. 13, 14 These reductions in LIC are essential for preventing long-term hepatic complications in beta-thalassemia patients.
Total bilirubin
Although the mean serum total bilirubin showed a slight increase from 1.05 mg/dl to 1.16 mg/dl, this change was not clinically significant and did not suggest worsening liver function. Monitoring bilirubin levels is essential to ensure no adverse impact on hepatic function, particularly when using chelation therapy. Studies have shown that fluctuations in bilirubin levels can occur but do not necessarily indicate hepatic dysfunction. 15 Regular follow-up with liver function tests, including bilirubin levels, remains a cornerstone in the management of patients on chelation therapy, ensuring early detection of any adverse effects while avoiding unnecessary concern over minor, non-clinically significant changes.
Pancreatic T2
The significant increase in pancreatic T2 from 15.96 ms to 20.23 ms (p=0.007) at the end of 12 months is significant. Pancreatic iron loading can lead to diabetes mellitus, a common complication in thalassemia patients. The improvement in pancreatic T2 in our study suggests a beneficial effect of DFX in reducing pancreatic iron deposition, thereby potentially mitigating the risk of diabetes. This finding is supported by research conducted by Noetzli et al where a significant higher frequency of glucose dysregulation was seen among patients having pancreatic iron overload compared to patients without pancreatic iron overload (71.8% vs. 15.0%; P < 0.0001). 16 In a multi centric Observational Study done by Alessia Pepe et al on the influence of Pancreatic Iron with Glucose Metabolism and With Cardiac Complications in Thalassemia Major patients with normal glucose metabolism had significantly higher global pancreas T2* values 14.31 ± 11.31 ms compared to those with impaired fasting glucose (IFG) 8.82 ± 6.23 ms, impaired glucose tolerance (IGT) 8.25 ± 5.03 ms, and diabetes 7.87 ± 4.45 ms. 17 This indicates a correlation between lower pancreatic T2* values and higher risk of glucose metabolism disorders and highlights the importance of reducing pancreatic iron to prevent endocrine complications.
Safety and tolerability
Our study observed a statistically significant increase in mean serum creatinine levels from 0.64 ± 0.14 mg/dL to 0.7 ± 0.13 mg/dL at the end of 6 months of treatment with Deferasirox (14 mg/kg), which returned to normal levels (0.63 mg/dL) at the end of 12 months (P=0.009). Despite this temporary increase in serum creatinine, patients did not experience any additional therapy-related adverse events throughout the study period Importantly, no therapy-related adverse events were reported throughout the study period, indicating that DFX was well-tolerated by the paediatric patients. This safety profile is crucial for long-term adherence and effectiveness of the therapy. Studies by Cappellini et al. and Taher et al. also reported favourable safety and tolerability profiles for DFX, reinforcing its suitability for long-term use in children. 18, 19 Comparison with Other Chelation Therapies: Our findings on the efficacy of DFX are consistent with studies comparing DFX to other chelation therapies such as Deferoxamine (DFO) and Deferiprone (DFP). While DFO remains a standard therapy, its requirement for parenteral administration limits its use, particularly in paediatric populations. DFP, although effective, has been associated with agranulocytosis and other adverse effects. 20 DFX, administered orally, offers a more convenient and well-tolerated option with comparable efficacy, as demonstrated in our study and corroborated by comparative studies. 21
Conclusion
Deferasirox has demonstrated significant efficacy in reducing iron overload in paediatric patients with transfusion-dependent beta-thalassemia over 12 months. The substantial improvements in serum ferritin, cardiac MRI T2*, LIC, transferrin saturation, and pancreatic T2, coupled with its excellent safety profile, support the use of DFX as a cornerstone in the management of iron overload in this vulnerable population. Our findings are consistent with and extend existing literature, reinforcing the role of DFX in improving clinical outcomes and quality of life for thalassemia patients. Continued monitoring
Limitations of Study
A large sample size is required to allow a more accurate assessment of this study
Main limitation of this study is the absence of a control arm
Longer-term studies are recommended to further establish the safety of deferosirox and optimize the dosing strategies.
Figure 1
Comparison between transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT)
Figure 2
Serum ferritin levels in transfusion dependent beta-thalassemia patients on Deferasirox (iron chelation therapy) at different time interval (n=22). p < 00009 as compared to baseline, (Paired Student's t-test)
Figure 3
Cardiac MRI T2 in transfusion dependent beta-thalassemia patients on Deferasirox (ironchelation therapy) at different time interval (n=22). p < 0016 as compared to baseline, (Paired Student's t-test)
