Deferoxamine Monotherapy Research Articles

Real-world experience with iron chelation therapy in transfusion-dependent thalassemia: impact of the oral chelators' era.

Iron overload is a common complication in patients with transfusion-dependent-thalassemia that can lead to end-organ damage. Management of iron overload has considerably evolved since the early 2000s with the approval of oral iron chelators and widespread use of MRI monitoring. We conducted a retrospective cohort study of 144 patients with transfusion-dependent-thalassemia treated at a single center in the US and followed since initiation of regular transfusion therapy. Patients who were receiving deferoxamine monotherapy and then switched to/added an oral chelator had a mean decrease in liver iron concentration (LIC) by 0.02mg/g dry weight (dw) per month (0.24mg/g dw per year) and a mean increase in cardiac T2* by 0.07ms per month (1.68ms per year) after starting an iron chelator (p < 0.001 for both). There was a statistically significant decrease in the proportion of patients with clinically-relevant cardiac iron overload (cardiac T2* < 20ms and < 10ms) from 2006-2010 to 2016-2020, with a trend towards a decrease in the proportion of patients with clinically-relevant hepatic iron overload (LIC > 15mg/g dw). The introduction of oral chelators has transformed management in patients with transfusion-dependent thalassemia and led to persistent improvements in iron burden over the years.

PD02 A Literature Review Of Treatment Schemes And Effects For Beta Thalassemia In China

IntroductionThe incidence of beta thalassemia varies greatly in different regions of China. Blood transfusion combined with iron chelation and hematopoietic stem cell transplantation (HSCT) is the main treatment for beta thalassemia in China. This study aimed to reveal the specific treatment schemes used for patients with beta thalassemia and to evaluate their effects.MethodsA search strategy was developed to identify articles published between 1 January 2010 and 30 August 2021 in the following literature databases: PubMed, Embase, the China National Knowledge Infrastructure, Wanfang Data, and the Chinese BioMedical Literature Database.ResultsThe most used iron chelation schemes in China for patients with beta thalassemia included deferoxamine (DFO) monotherapy, deferiprone (DFP) monotherapy, deferasirox (DFX) monotherapy, and combinations of DFP and DFO. Most studies reported that combinations of DFP, DFO, and DFX monotherapy performed better than DFO or DFP monotherapy alone in reducing the blood, heart, and liver iron load. However, the adverse effects of iron chelation affected patient compliance with treatment to a certain extent. Stem cells for patients receiving HSCT in China were mainly donated by human leukocyte antigen (HLA)-matched siblings or unrelated individuals. The five-year overall survival rate after HSCT ranged from 83 to 90 percent, while the five-year beta thalassemia-free survival rate ranged from 65 to 87 percent. Graft-versus-host disease and infection were the most common serious complications experienced by transplant recipients.ConclusionsFor patients in China with beta thalassemia, the most effective iron chelation treatment schemes were combinations of DFP, DFO, and DFX monotherapy. HSCT from HLA-matched siblings or unrelated donors resulted in a significant improvement in the cure rate for beta thalassemia. However, patients still need safer and more effective innovative treatments, and further evidence on existing treatments needs to be generated from larger scale studies in the Chinese population.

Effect of drug use calendar on adherence to iron chelation therapy in young thalassemia patients.

Background:Regular blood transfusions in thalassemia patients can lead to severe complications and iron chelation therapy is required as a treatment. Thalassemia is common in Thailand and the drugs used in iron chelation therapy are deferoxamine and deferiprone. Adherence to the therapy is a key factor for treatment success.Objective:To assess the impact of a drug use calendar on deferiprone and deferoxamine adherence in young thalassemia patients.Methods:A total of 86 young thalassemia outpatients at a Thai tertiary care hospital were recruited into the study. Patients were stratified into two groups based on self-assessment of adherence using a visual analogue scale. One group (n=41) was given a calendar with the schedule of drug use in addition to counselling as standard pharmaceutical care. The second group (n=45) only received the counselling. Adherence to iron chelation therapy was assessed by deferiprone pill or deferoxamine vial counts on six visits (V1 to V6) and results were compared between visits and groups using a multilevel linear regression model. Change in serum ferritin levels after 6 visits (n = 81) were compared using a linear regression model.Results:Adherence significantly increased in both the calendar and non-calendar groups for deferiprone mono- and combination-therapy and for deferoxamine monotherapy. In the calendar groups, average adherence increased by between 2.05 and 5.66% per visit compared to increases of 0.31 to3.92% per visit in the non-calendar groups. A significant difference in the increase in adherence per visit between the calendar and non-calendar groups was only observed for deferiprone monotherapy (3.03% SEM = 0.49vs 1.42% SEM =0.49, respectively, P-value = 0.0078). The serum ferritin level decreased in the calendar group by 20.25ng/mL (SEM = 23.80) and increased in the non-calendar group by 59.63 ng/mL (SEM = 23.01, P-value = 0.0147).Conclusion:Provision of a drug use calendar improved adherence to deferoxamine and deferiprone and decreased serum ferritin levels in young Thai thalassemia patients over the improvements obtained from standard counselling.

Combined chelation with high-dose deferiprone and deferoxamine to improve survival and restore cardiac function effectively in patients with transfusion-dependent thalassemia presenting severe cardiac complications.

Iron overload-induced cardiomyopathy is the leading cause of death in patients with transfusion-dependent thalassemia (TDT). The mortality is extremely high in these patients with severe cardiac complications, and how to rescue them remains a challenge. It is reasonable to use combined chelation with deferiprone (L1) and deferoxamine (DFO) because of their shuttle and synergistic effects on iron chelation. Here, seven consecutive patients with TDT who had severe cardiac complications between 2002 and 2019 and received combined chelation therapy with oral high-dose L1 (100mg/kg/day) and continuous 24-h DFO infusion (50mg/kg/day) in our hospital were reported. Survival for eight consecutive patients receiving DFO monotherapy for their severe cardiac complications between 1984 and 2001 was compared. We found that combined chelation therapy with high-dose L1 and DFO was efficient to improve survival and cardiac function in patients with TDT presenting severe cardiac complications. Reversal of arrhythmia to sinus rhythm was noted in all patients. Their 1-month follow-up left ventricular ejection fraction increased significantly (P < 0.001). There were no deaths, and all patients were discharged from hospital with good quality of life. In contrast, all the eight patients receiving DFO monotherapy died (P < 0.001). Accordingly, combined chelation therapy with high-dose L1 and DFO should be considered in patients with TDT presenting cardiac complications.

ECONOMIC EVALUATION OF CHELATION REGIMENS FOR β--THALASSEMIA MAJOR: A SYSTEMATIC REVIEW

BackgroundDeferoxamine (DFO) or Deferiprone (DFP) or Deferasirox (DFX) monotherapy and DFO and DFP combination therapy (DFO+DFP) were four commonly implemented now chelation regimens for the iron overloaded of β-thalassemia major. This systematic review aims to determine the cost-effectiveness of four chelation regimens and provide evidence for the rational use of chelation regimens for β-thalassemia major therapy in the clinic.MethodsA systematic literature search in MEDLINE, EMBASE, the Cochrane Library, China Biology Medicine, China National Knowledge Infrastructure, VIP Data, and WanFang Data was conducted in April 2018. In addition, a manual search was performed. Two researchers, working independently, selected the papers, extracted the data, and assessed the methodological quality of the included documents. Each included paper was evaluated using a checklist developed by Drummond et al.ResultsThe number of records was initially 968, and eight papers met the final eligibility criteria. All the included eight papers were cost-utility analyses, and their methodological quality was fair. In these eight papers, nineteen studies were present. Nine studies of DFX versus DFO had contradictory results. Out of the nineteen studies, three studies of DFX versus DFP established that using DFP was cost-effective. Three studies of DFP versus DFO proved that using DFP was cost-effective. One survey of DFO+DFP versus DFO found that using DFO was cost-effective. One study of DFO+DFP versus DFP found that using DFP was cost-effective. Moreover, there were two studies of DFO+DFP versus DFX, but we cannot be sure which one of two chelation regimens was cost-effective.ConclusionIn brief, DFP is cost-effective, followed by DFO or DFX, when an iron chelator is to be used alone for β-thalassemia iron overload treatment. All studies that compared DFO+DFP with DFO (or DFP) monotherapy established that the DFO+DFP was not cost-effective. Existing studies about DFO+DFP versus DFX could not prove which one of two chelation regimens was cost-effective. However, due to the low number of DFO+DFP versus DFO (or DFP or DFX) monotherapy studies, more extensive, high-quality research is required for further analysis and confirmation of our findings. Moreover, the cost-effectiveness is not an absolute issue when in different countries (regions) the results are opposite for other countries (regions). As a result, the local/national context had a substantial influence on the results of the pharmacoeconomic evaluation.

Cost-Utility Analysis of Three Iron Chelators Used in Monotherapy for the Treatment of Chronic Iron Overload in β-Thalassaemia Major Patients: An Italian Perspective.

Deferiprone (DFP), deferasirox (DFX) and deferoxamine (DFO) are used in thalassaemia major (TM) patients to treat chronic iron overload. We evaluated the cost-effectiveness of DFP, compared with DFX and DFO monotherapy, from an Italian healthcare system perspective. A Markov model was used over a time horizon of 5years. Italian-specific cost data were combined with Italian efficacy data. Costs and quality-adjusted life years (QALYs) were calculated for each treatment, with cost-effectiveness expressed as cost per QALY. In all scenarios modelled, DFP was the dominant treatment strategy. Sensitivity analyses showed that DFP dominated the other treatments with a >99% likelihood of being cost-effective against DFX and DFO at a willingness to pay threshold of €20,000 per QALY. DFP was the dominant and most cost-effective treatment for managing chronic iron overload in TM patients. Its use can result in substantial cost savings for the Italian healthcare system.

Comparison of iron chelation effects of deferoxamine, deferasirox, and combination of deferoxamine and deferiprone on liver and cardiac T2* MRI in thalassemia maior.

Background: Cardiac complications due to iron overload are the most common cause of death in patients with thalassemia major. The aim of this study was to compare iron chelation effects of deferoxamine, deferasirox, and combination of deferoxamine and deferiprone on cardiac and liver iron load measured by T2* MRI.Methods:In this study, 108 patients with thalassemia major aged over 10 years who had iron overload in cardiac T2* MRI were studied in terms of iron chelators efficacy on the reduction of myocardial siderosis. The first group received deferoxamine, the second group only deferasirox, and the third group, a combination of deferoxamine and deferiprone. Myocardial iron was measured at baseline and 12 months later through T2* MRI technique.Results:The three groups were similar in terms of age, gender, ferritin level, and mean myocardial T2* at baseline. In the deferoxamine group, myocardial T2* was increased from 12.0±4.1 ms at baseline to 13.5±8.4 ms at 12 months (p=0.10). Significant improvement was observed in myocardial T2* of the deferasirox group (p<0.001). In the combined treatment group, myocardial T2* was significantly increased (p<0.001). These differences among the three groups were not significant at the 12 months. A significant improvement was observed in liver T2* at 12 months compared to baseline in the deferasirox and the combination group.Conclusion: In comparison to deferoxamine monotherapy, combination therapy and deferasirox monotherapy have a significant impact on reducing iron overload and improvement of myocardial and liver T2* MRI.

A Systematic Review and Meta-Analysis of Deferiprone Monotherapy and in Combination with Deferoxamine for Reduction of Iron Overload in Chronically Transfused Patients with β-Thalassemia

β-Thalassemia major (β-TM) patients require life-long blood transfusions, resulting in iron overload with multi-organ morbidity and mortality. Evidence from small randomized controlled trials (RCTs) published to date for deferiprone (DFP) monotherapy or in combination with deferoxamine (DFO) is unclear. We summarized evidence on the efficacy of DFP monotherapy compared to DFO, and DFP-DFO combination therapy compared to DFP or DFO monotherapy in chronically transfused β-TM. We searched four electronic databases and examined the grey literature. Two authors independently assessed trial quality and extracted data. We calculated the relative risk for dichotomous outcomes and mean difference (MD) for continuous outcomes. We identified 15 RCTs (1003 participants) that met the inclusion criteria. Deferiprone was more efficacious than DFO in improving cardiac ejection fraction [MD 2.88, 95% CI (95% confidence interval) 1.12 to 4.64, p = 0.001) and endocrine dysfunction (MD 0.09, 95% CI 0.08 to 0.10, p < 0.00001). The DFP-DFO combination therapy was more efficacious than DFP or DFO monotherapy in improving cardiac ejection fraction (MD 5.67, 95% CI 1.32 to 10.02, p = 0.008). There was no significant difference in all other outcomes examined. Meta-analysis on changes in myocardial iron content was not possible due to differences in data presentation. The quality of evidence for all outcomes was low. There is currently insufficient evidence to show that DFP is superior to DFO in the treatment of iron overload. The use of DFP must be weighed against the potential side-effects, patient compliance and preference. Large RCTs with clinically relevant outcomes are required.

Combination therapy of deferasirox and deferoxamine shows significant improvements in markers of iron overload in a patient with β‐thalassemia major and severe iron burden

Iron overload is a common complication of patients with β-thalassemia major (TM). Despite the availability of three iron chelators, deferoxamine (DFO), deferiprone (DFP), and deferasirox (DFX), some patients fail to respond adequately to monotherapy with any of them. We report a case of TM who had refractory severe iron overload and was successfully and safely chelated with the combination of DFX with DFO. A 40-year-old male with β-TM, who had been regularly transfused from the age of 2, had been administered in the past iron chelation with DFO, DFP, and DFX monotherapy, without major improvement on his iron overload status. Liver and cardiac magnetic resonance imaging (MRI) revealed severe iron overload, while serum ferritin was persistently greater than 2500 μg/L. After the patient gave informed consent, he was administered combination therapy of DFX at 30 mg/kg/day for 7 days per week and DFO at 2500 mg/day for 4 days every week and routinely followed up for compliance. Eighteen months later, serum ferritin was reduced to 680 μg/L, while both liver and cardiac MRI T2* values improved, reflecting lower iron overload. The combination regimen was well tolerated and no adverse events were documented. This is the first official report of simultaneous daily administration of the two iron chelators DFX and DFO that demonstrates the beneficial effect of the combination on heart and liver hemosiderosis. If our observation is confirmed in more patients, this combination could constitute a useful option in tailoring individual chelation therapy for β-TM patients with iron overload.

Clinical efficacy and safety evaluation of tailoring iron chelation practice in thalassaemia patients from Asia-Pacific: a subanalysis of the EPIC study of deferasirox

Although thalassaemia is highly prevalent in the Asia-Pacific region, clinical data on efficacy and safety profiles of deferasirox in patients from this region are rather limited. Recently, data from the multicentre Evaluation of Patients' Iron Chelation with Exjade (EPIC) study in 1744 patients with different anaemias has provided an opportunity to analyse 1115 thalassaemia patients, of whom 444 patients were from five countries in the Asia-Pacific region (AP) for whom thalassaemia management and choice of iron chelators were similar. Compared to the rest of the world (ROW), baseline clinical data showed that the AP group appeared to be more loaded with iron (3745.0 vs. 2822.0 ng/ml) and had a higher proportion on deferoxamine monotherapy prior to the study (82.9 vs. 58.9%). Using a starting deferasirox dose based on transfusional iron intake and tailoring it to individual patient response, clinical efficacy based on serum ferritin reduction in AP and ROW thalassaemia patients was similar. Interestingly, the AP group developed a higher incidence of drug-related skin rash compared to ROW (18.0 vs. 7.2%), which may indicate different pharmacogenetic backgrounds in the two populations. Our analysis confirms that, with appropriate adjustment of dose, deferasirox can be clinically effective across different regions, with manageable side effects.

Cardiac events and cardiac T2* in Egyptian children and young adults with β-thalassemia major taking deferoxamine

Cardiac events and death are not uncommon in adults with beta-thalassemia (b-TM) taking deferoxamine (DFO) monotherapy because of poor compliance and possibly the less effectiveness of DFO in controlling cardiac iron overload. We sought to assess compliance with DFO, the percentage of shift to other iron chelators, and the occurrence of cardiac siderosis, and cardiac events and death in b-TM patients on DFO monotherapy. Prospective, observational, 10-year follow-up of patients attending Ain Shams Thalassemia Unit, Cairo, Egypt. For all b-TM patients aged 2-18 years attending the unit during January 1998 and taking DFO, we recorded all cardiac events (whether fatal or not) during January 2008. All patients still on DFO monotherapy and with a normal EKG and not showing symptoms or signs suggestive of heart failure (HF) were evaluated for cardiac siderosis by T2*. Of 412 patients, only 126 (31%) were still taking DFO monotherapy (only 43% of those were compliant), 136 were taking combined DFO and deferiprone (DFP), 72 were taking DFP and 32 were taking deferasirox (DFX). Twenty-one were lost to follow-up and 25 died (10 cardiac). Eight of ten cardiac deaths and 12 of 15 non-cardiac deaths were in the DFO monotherapy group. Those taking DFO monotherapy with no HF and left ventricular ejection fraction (LVEF) by T2* >56% had a median age of 19 years and 56% were males; cardiac T2* was less than 20 ms in 30 (22%), 10-20 ms in 20 (14.7%) and less than 10 ms in 10 (7.3%). LVEF ranged from 58%-76% (median 64%). Forty percent of T2* patients less than 10 ms were compliant with DFO. Fifty-eight percent of patients on DFO monotherapy were noncompliant, but even compliance did not prevent severe cardiac siderosis and most cardiac events (whether fatal or not) that occurred in the DFO monotherapy group.

Increased survival and reversion of iron-induced cardiac disease in patients with thalassemia major receiving intensive combined chelation therapy as compared to desferoxamine alone

Myocardial iron overload is the leading cause of death in patients with β-thalassemia major. An intensification monotherapy with deferoxamine (DFO) as well as a combination therapy with DFO and deferiprone (DFP) reduces myocardial iron and improves cardiac function. However, the prognosis for thalassemia major patients with established cardiac disease switched from DFO monotherapy to combined DFP/DFO chelation is unknown. Twenty-eight thalassemia major patients with cardiac disease were enrolled in a prospective study lasting 42 ± 6 months. Fifteen (9 high-ferritin and 6 low-ferritin) were placed on DFP/DFO (DFP, 75 mg/kg t.i.d.; DFO, 40–50 mg/kg over 8–12 h at night 5–7 days/week), while 13 (5 high- and 8 low-ferritin) received DFO alone. No cardiac events were observed among high-ferritin patients on combination therapy, whereas 4 cardiac events ( p = 0.0049), including three deaths, occurred in high-ferritin patients on DFO monotherapy. These findings demonstrate that in thalassemia major patients with well-established cardiac disease combined iron-chelation therapy with DFP/DFO is superior to DFO monotherapy.

Effect of Combined Chelation Therapy with Deferiprone and Deferoxamine on Left Ventricular Diastolic Function in Adult β-Thalassemia Major Patients

β-Thalassemia major (β-TM), patients, asymptomatic and with preserved left ventricular ejection fraction (LVEF) were studied echocardiographically. Group A (26 patients), on deferiprone (L1) and deferoxamine (DFO) combination therapy (L1: 80 ± 27 mg/kg/day, DFO: 160 ± 87 mg/kg/week) and group B (35 patients) on DFO monotherapy (240 ± 40 mg/kg/week) for the last 2 years were compared. Another group, C (14 patients), switched to L1 (74 ± 15 mg/kg/day) plus DFO (158 ± 48 mg/kg/week) for 20–30 months, was prospectively studied for 2 years.In group A, MRI T2* values were increased and improved in group C during follow-up. The LVEF was better in group A than in group B, while such an improvement was also detected in the group C follow-up study. The Tissue Doppler study E′ velocity and E/E′ ratio was not different. Similarly, in the group C follow-up no significant change in E/E′ ratio was detected. It seems that although LVEF significantly improves with combined therapy, diastolic function indexes do not show a similar change.

Socio-psychological impact of infused iron chelation therapy with deferoxamine in metropolitan France: ISOSFER study results

Deferoxamine (DFO) is an iron chelator used to treat iron overload in patients receiving chronic blood transfusions, and is usually administered as overnight subcutaneous infusions. ISOSFER was a prospective, observational, cross-sectional study conducted in metropolitan France that evaluated patient characteristics, quality of life (QoL), compliance and patient satisfaction with DFO monotherapy. Of 70 patients with either thalassemia, sickle cell disease or myelodysplastic syndromes, 30% were 'satisfied' or 'very satisfied' with DFO. Patients' SF-36 scores were lower than those of the general French population, and lower among patients with comorbidities and those dissatisfied with treatment. Although 72% of patients had good compliance to DFO, 57% reported missing at least one infusion in the previous month, and 82% of patients expressed a preference for oral therapy. These results suggest that QoL is severely compromised in patients receiving DFO, and that compliance is not optimal.

The Effects of 24 Hour Continuous Deferoxamine Intensification on Serum Creatinine.

BACKGROUND: With new chelation regimes such as deferasirox, there has been interest in their effects on serum creatinine, as about one third of patients show a small non-progressive increase within a few weeks of starting treatment. A question arises as to whether creatinine increases occur with other modalities of chelation therapy. The effects of deferoxamine (DFO) on serum creatinine have not been widely studied, particularly when intensive chelation regimes are used with 24 hour (h) exposure. Intensified 24h DFO for patients with high risk iron overload has been in use for selected patients for over 20 years. However, whilst factors leading to retinal and ototoxicity are well described, effects on serum creatinine are largely confined to case reports. We postulated that small increments in serum creatinine might be an inevitable effect of treatment intensification. We therefore undertook retrospectively to examine the effects on serum creatinine in patients in whom standard DFO therapy (40mg/kg as 8–10h infusions 5 days/ week) was switched to an intensive DFO monotherapy regime with 24h/day therapy.PATIENTS AND METHODS: We examined the records of 10 patients with transfusion dependent thalassaemia attending the haematology department at University College London Hospitals, between 1989 and 2008, who required an intensification of their DFO regime as a result of failure to control their iron burden with their existing regime. Nine out of the 10 patients required portacath insertion for their DFO to be delivered intravenously, the tenth patient was switched to subcutaneous DFO administered 24h/ day. The patient characteristics were as follows: 8 male and 2 female. Two had thalassaemia intermedia and the rest had thalassaemia major. Those with a portacath were commenced on warfarin as thromboprophylaxis for the portacath. Co-morbidities for the patients included splenectomy (2); diabetes (2); cardiac failure (3); arrhythmias (2). The mean dose of deferoxamine administered was 52mg/kg/24h (9 of the patients had doses between 35–60 mg/kg/24h and only 1 patient had a dose of 100 mg/kg/24h).RESULTS: The results of the study revealed a mean ferritin of 6113.2μg/L ± 1681.3 and 3910.5μg/L ± 1438.4 pre and post intensification of DFO respectively. Of the 10 patients, 6 of them displayed an increase in creatinine of over 25% of their original level on standard DFO, the other 4 also had an increase albeit a more modest one. The increase in creatinine did not correlate with the dose of DFO given. The creatinine pre-intensification showed a mean of 62.3μmol/L ± 10.19 and post intensification showed 92.3μmol/L ± 11.17. This was a statistically significant difference with a p value of 0.0016 using a paired student t test. No patient went on to develop progressive renal dysfunction and creatinine returned to baseline in all patients when the regime returned to standard therapy.CONCLUSIONS: We conclude that intensification of DFO using 24h chelation results in small increments in serum creatinine, even when doses are as low as 40–70mg/kg. The findings suggest that increments in creatinine with chelation therapy are more frequent than hitherto recognised and may be a general effect of continuous chelation therapy. These changes were reversible on returning to original intermittent DFO. While none of these patients developed permanent changes, we propose that patients who are commenced on DFO, especially at continuous intensified doses, should have their creatinine measured on a regular basis, and caution should be employed with those patients who have borderline high creatinine.

Long Term Comparative Studies in Thalassemia Patients Treated with Deferoxamine or a Deferoxamine/Deferiprone Combination. Identification of Effective Chelation Therapy Protocols

For the past 2–6 years, two groups of thalassemia patients, one of 16 patients on deferoxamine (DFO) monotherapy (35–80 mg/kg, 2–5 days/week) and the other group comprising 19 patients on a deferiprone (L1) and DFO combination therapy (L1 75–100 mg/kg/day and DFO 30–60 mg/kg, 1–5 days/week), have been studied and compared before and after the introduction of the combination therapy. The patients on the combination therapy were mainly those not complying or experiencing toxicity with DFO. The effects of chelation therapy on iron load was monitored using regular serum ferritin measurements and also magnetic resonance imaging (MRI) T2* relaxation time measurements at the end of the study. In both groups, cardiac MRI T2* levels were within the normal range (>19 ms) in more than 75% of the patients. There was a substantial improvement in serum ferritin levels and normalization of the MRI T2* levels of the liver in many cases treated with the combination therapy at effective doses by comparison to the DFO group, where the serum ferritin and MRI T2* levels were largely unchanged. It would appear that the major overall determining factor in the rapid clearance of excess iron in thalassemia patients and the maintenance of normal iron stores is the selection and implementation of effective chelation dose protocols. The International Committee on Chelation (ICOC) combination protocol L1 (80–110 mg/kg/day)/DFO (40–60 mg/kg at least 3 days per week) and to a lesser extent, DFO monotherapy at about 50 mg/kg/day, 5 days/week, appears to achieve this goal.

Pattern of iron chelation therapy in Egyptian beta thalassemic patients: Mansoura University Children's Hospital experience

Background: The simultaneous use of deferoxamine (DFO) and deferiprone (DFP) has an additive effect in iron excretion in transfusion-dependent thalassemic patients.Aim of the work: To evaluate the efficacy and safety of a prospective alternating therapy with DFO and DFP in patients with β-thalassemia major (TM) and increased serum ferritin with DFO monotherapy alone.Patient and methods: Sixty patients with β-TM (mean age ± SD, 13.05 ± 6.1, range 10–20 years) with iron overload (serum ferritin > 2000 ng/ml) were studied. They received DFO at a daily dose of 40 mg/kg/day for 5–7 nights/week for the past several years. These patients were randomly assigned either to continue treatment with DFO alone (DFO group, n = 30) or prospectively receive additional alternating therapy with DFP at 75 mg/kg/day for 4 days/week and DFO for the other 2 days/week (alternating therapy group, n = 30). The efficacy of both groups was assessed by measurements of serum ferritin, echocardiography, and 24 h urine iron excretion (UIE) levels throughout 1 year follow-up.Results: In the 60 evaluable patients, the mean serum ferritin (± SD) fell dramatically from 4500 (± 1250) ng/ml at the start of the study to 1250 (± 750) ng/ml (alternate therapy group; P < 0.001) at the end of the study. There was also a significant improvement in the myocardial function as assessed by the ejection fraction (P < 0.002) and fractional shortening (P < 0.01) in those patients on alternate therapy for 1 year. Their mean urinary iron excretion elevated from 0.41 ± 0.27 to 0.76 ± 0.49 mg/kg/24 h (P < 0.003). There was a significant difference between both groups as regard the studied parameters at the end of the study. Whereas, there was no statistical difference as regard the studied parameters at the start and the end of the study in the DFO group. No significant adverse effects had occurred in both groups that necessitated withdrawal from the study.Conclusions: β-Thalassemic major patients with transfusional iron overload can be safely and effectively treated with an alternate therapy of DFO/DFP with a progressive fall in the mean serum ferritin and significant improvement of myocardial performance.

Concepts and goals in the management of transfusional iron overload

In this review, current concepts and goals of iron chelation therapy for thalassemias, sickle cell disease, and myelodysplastic syndromes are discussed. The primary goal of iron chelation therapy is to prevent the accumulation of iron reaching harmful levels by matching iron intake from blood transfusion, with iron excreted by iron chelation. Over 30 years of experience with deferoxamine has shown iron chelation to be an effective therapeutic modality. However, chelation efficiency is limited because most of the body's iron stores are not directly chelatable, and only a small fraction of body iron is chelatable at any moment. Once iron has been deposited in organs other than the liver, for example the heart, removal by chelation is slow and inefficient. Chelation efficiency can be improved by designing regimes where chelators are available 24 hr a day to bind labile iron pools in cells and plasma. Deferoxamine has a short plasma half-life and the parenteral infusions required to achieve steady plasma levels are demanding, with consequent variable adherence to therapy. Once-daily oral administration of deferasirox achieves continuous chelation with trough concentrations sufficient to decrease plasma labile iron species progressively, and achieves an efficiency of chelation not obtainable with deferiprone or deferoxamine monotherapy.

Randomised Prospective Evaluation of Iron Balance, Chelation Efficiency, Urine Excretion and NTBI Progression with Deferiprone (DFP) or Deferoxamine (DFO) Monotherapy or with Combined DFP Plus DFO.

Rationale. The relative effects of monotherapy regimes with oral DFP or sc DFO or combinations of these drugs, on chelation efficiency, iron balance, plasma non-transferrin bound iron (NTBI) and the proportion and speciation of urine iron, have not been compared previously in prospective randomised trials. By examining these variables together in a single study, insights into the effectiveness and mechanisms of action of mono or combination regimens can be gained. Design. A total of 25 patients (pts) with thalassaemia major were randomised into one of the following 3 arms: DFP (LIPOMED AG, Switzerland) was given at a daily dose of 75 mg/kg either in combination with DFO (40–50 mg/kg twice weekly) or as single agent, and pts registered in the DFO control arm received 40–50 mg/kg sc DFO 5 days a week. All pts had been treated with DFO prior to the study.Methodology. Liver iron concentration (LIC) was measured by biopsy at baseline and after 1 year. Total iron excretion (IE)/day was calculated as (iron transfused/year (mg) + (LIC at To - LIC at T1y) x 10.6 x body wt in Kg) /number of days treatment. Chelation efficiency (%) was calculated as [IE (in mg/kg/day)/chelator dose (in mg/kg/day)] x [molecular weight of the respective chelator(s)/56]x n x 100, where 56 is the molecular weight of iron and n is 3 or 1 with DFP and DFO respectively. The average urinary iron excretion (UIE) (weeks 1, 12, 26, 38 and 54) was calculated from atomic absorption measurements. In patients receiving combination, UIE was measured during both days of monotherapy and combination therapy. The % UIE was calculated from mean UIE divided by total IE. In patients receiving DFO with or without DFP, the concentration of feroxamine species were measured in urine, collected into aluminised containers. Plasma NTBI was measured by HPLC at baseline and at weeks 1, 12, 26 and 54 standardised to blood transfusion interval.Results. The results show that DFO sc 5 days a week was the regimen associated with the largest and most efficient IE and stabilised NTBI after 1 year. Single agent DFP showed the lowest IE and efficiency, and a significant increase in NTBI (* p=0.001). The addition of sc DFO two days a week to DFP resulted in significant increase in IE (^ p=0.03) and stabilised NTBI. The proportion of UIE was significantly lower with DFO than with DFP regimens. UIE on the days of combination (0.89± 0.14mg/kg/d) was significantly higher than on days of DFP monotherapy (0.41 ±0.09 mg/kg/d) (p=0.002). Speciation of urinary iron showed that the proportion of DFO bound to iron was higher on days of combination treatment than with DFO monotherapy, consistent with shuttling of iron onto DFO by DFP.Conclusions. The addition of sc DFO twice weekly to DFP at 75mg/kg po is a regimen which appears as effective at producing iron balance as DFO given 5 days a week at standard doses. Both regimens are more effective at stabilising NTBI, and achieving iron balance than DFP at 75mg/kg/day. When DFP is combined with DFO, iron excretion appears to be mainly by the urinary route as feroxamine.Treatment RegimenIron Excretion mg/kg/dNTBI change μMEfficiency (%) Mean over studyUrine Iron (%) Mean over studyDFP (n=12)0.56±0.093.00±0.53 *6.65±0.9998±14.8DFO (n=5)0.77±0.250.72±0.4523.1±10.728±10.3DFP+DFO (n=8)0.69±0.09 ^0.84±0.877.34±0.9184±14.6

Objectives and Mechanism of Iron Chelation Therapy

Prevention of cardiac mortality is the most important beneficial effect of iron chelation therapy. Unfortunately, compliance with the rigorous requirements of daily subcutaneous deferoxamine (DFO) infusions is still a serious limiting factor in treatment success. The development of orally effective iron chelators such as deferiprone and ICL670 is intended to improve compliance. Although total iron excretion with deferiprone is somewhat less than with DFO, deferiprone may have a better cardioprotective effect than DFO due to deferiprone's ability to penetrate cell membranes. Recent clinical studies indicate that oral ICL670 treatment is well tolerated and is as effective as parenteral DFO used at the standard dose of 40 mg/kg of body weight/day. Thus, for the patient with transfusional iron overload in whom results of DFO treatment are unsatisfactory, several orally effective agents are now available to avoid serious organ damage. Finally, combined chelation treatment is emerging as a reasonable alternative to chelator monotherapy. Combining a weak chelator that has a better ability to penetrate cells with a stronger chelator that penetrates cells poorly but has a more efficient urinary excretion may result in improved therapeutic effect through iron shuttling between the two compounds. The efficacy of combined chelation treatment is additive and offers an increased likelihood of success in patients previously failing DFO or deferiprone monotherapy.