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 Table of Contents  
ORIGINAL ARTICLE
Year : 2013  |  Volume : 38  |  Issue : 2  |  Page : 51-55

Subcutaneous iron chelation therapy, oral iron chelation therapy, or both in patients with thalassemia?


1 Department of Pediatrics, Faculty of Medicine, Children & Obstetrics and Gynecology Hospital, Minia University, Minia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Children & Obstetrics and Gynecology Hospital, Minia University, Minia, Egypt

Date of Submission31-Oct-2012
Date of Acceptance11-Feb-2012
Date of Web Publication20-Jun-2014

Correspondence Address:
Gihan M. Babrs
Department of Pediatrics, Faculty of Medicine, Children & Obstetrics and Gynecology Hospital, Minia University, 61111 Minia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.7123/01.EJH.0000427962.62047.43

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  Abstract 

Background

This study aimed to compare the efficacy of different iron-chelating agents, namely deferoxamine (DFO), deferiprone (DFP), and deferasirox and combined DFO and DFP in reducing serum ferritin levels in thalassemic patients attending the Pediatric Hematology Clinic of the Children and Obstetrics and Gynecology Hospital, Minia University.

Patients and methods

A total of 57 patients with thalassemia major attending the Pediatric Hematology Clinic of Minia University were included in the study. They were classified into four groups according to type of chelation: the DFO group included 12 patients, the DFP group included 18 patients, the deferasirox group included 15 patients, and the combined DFO and DFP group included 12 patients. The patients were subjected to thorough history taking, clinical examination, and laboratory investigation (complete blood count, liver function and renal function tests, and levels of hepatitis B surface antigen, hepatitis C antibody, and initial serum ferritin at the start of the study and final serum ferritin levels after 1 year of chelation).

Results

The mean serum ferritin levels decreased significantly in all groups after 1 year (P<0.001), with more reduction in the combined therapy group. Four (22.2%) patients developed elevated liver transaminases and six (33.3%) developed mild bone pain and arthralgia during treatment with oral DFP. However, none of our patients developed neutropenia/agranulocytosis or significant gastrointestinal tract symptoms. There were no detectable side effects on administering deferasirox, except for some gastrointestinal tract pain that improved with continued treatment.

Conclusion

The three iron-chelating agents are effective in reducing the serum ferritin levels in thalassemic children, with the combined DFO and DFP therapy being more effective.

Keywords: deferasirox, deferiprone, deferoxamine, iron chelation, thalassemia


How to cite this article:
Babrs GM, Abd El-Hakeem MA. Subcutaneous iron chelation therapy, oral iron chelation therapy, or both in patients with thalassemia?. Egypt J Haematol 2013;38:51-5

How to cite this URL:
Babrs GM, Abd El-Hakeem MA. Subcutaneous iron chelation therapy, oral iron chelation therapy, or both in patients with thalassemia?. Egypt J Haematol [serial online] 2013 [cited 2019 Dec 8];38:51-5. Available from: http://www.ehj.eg.net/text.asp?2013/38/2/51/128296


  Introduction Top


Globally, it has been reported that there are at least 60 000 individuals born with thalassemia major each year 1. Regular blood transfusions are mandatory for long-term survival, but over a period of years, these cause a secondary state of tissue iron overload 2 and progressive organ failure as a result of cumulative iron deposition 3.

Morbidity and mortality in thalassemia are linked closely to the adequacy of chelation. Recent evidence from Europe has shown that by normalizing the iron stores, not only are new morbidities prevented but reversal of many complications such as cardiac failure, hypothyroidism, hypogonadism, impaired glucose tolerance, and type 2 diabetes can also occur, improving survival and patients’ quality of life 4. Three chelators are currently available worldwide, namely deferoxamine (DFO), deferasirox, and deferiprone (DFP) 5.

Despite the availability of three iron chelators, some patients fail to respond adequately to monotherapy with any of them 6. DFO was the first iron chelator introduced into clinical practice. Although effective, there are significant challenges associated with its use that can result in noncompliance 7.

DFP was initially introduced in Europe during the 1980s and was the first oral chelator to be used for the treatment of iron overload 8,9. It has advantages over ‘gold standard’ DFO including: oral mode of administration, better compliance, more affordability, and similar efficacy in reducing the iron burden in patients with severe hemosiderosis 10–14. Moreover, studies have shown a reduction or stabilization of serum ferritin levels and liver iron concentrations in most, but not all, patients with a transfusional iron overload 15. Deferasirox in doses of 20–30 mg/kg/day has been shown to have an efficacy similar to DFO with regard to the reduction in liver iron concentration and serum ferritin levels in a large randomized trial on thalassemia major 16.

Finally, comparative effectiveness trials may help to determine the ideal strategy (e.g. intensification of monotherapy or combined therapy) for treating various scenarios of organ-specific iron loading.

This study was carried out to compare the efficacy of different iron-chelating agents, namely DFO, DFP, and deferasirox when used as monotherapy and as a combination of DFO with DFP in patients with thalassemia attending the Minia University Pediatrics Hematology Clinic.


  Patients and methods Top


This study was a prospective nonblinded study carried out at the Children and Obstetrics and Gynecology Hospital, Minia University, from January 2011 to January 2012. A total of 57 patients with the diagnosis of thalassemia major attending the Minia University Pediatric Hematology Clinic were included in the study after an informed consent was obtained from all patients to participate in this study. The patients were selected based on a systematic random selection. Thalassemic patients with serum ferritin levels of more than 1000 ng/ml were included in the study. The history (age, sex, age at first blood transfusion, and frequency of blood transfusion), baseline physical and clinical examination findings, and laboratory data including a complete blood count and levels of aspartate aminotransferase (AST), alanine aminotransferase, hepatitis B surface antigen, and hepatitis C antibody were recorded. The patients were divided into four groups according to the type of iron chelation therapy used: the DFO group included 12 thalassemic children who received DFO as chelation therapy (50 mg/kg/day) by subcutaneous infusion during a 12-h period overnight for 5 days a week; the DFP group included 18 children with thalassemia who received DFP 7 days a week at a dose of 75 mg/kg/day in two to three divided doses; the deferasirox group included 15 patients who received deferasirox 20–30 mg/kg/day; and the combination group comprised 12 patients who received a combination therapy of DFO and DFP. The patients of the combination group were already on DFO but with no significant improvement in their serum ferritin values and hence DFP was introduced in their therapy. They received both drugs on the same day, generally with DFP administered in doses of 75 mg/kg/day (in three divided doses) daily and DFO in doses of 20–50 mg/kg/day subcutaneously administered 2 days a week.

The patients were followed up over a period of 1 year. A complete blood count was performed every 2 weeks and on the day of the transfusion for all patients during the study period. Adverse events were recorded in the patient’s files. The primary outcome variable was serum ferritin level at the start and at the end of the study. Determination of serum ferritin levels was carried out using enzyme-linked fluorescent assay using a VIDAS Ferritin automated quantitative test manufactured by Biomerieux SA (Marcy-PEtoile, France).


  Statistical methods Top


The data were analyzed using the SPSS version 13 17 Windows program (SPSS Inc., Chicago, Illinois, USA) for descriptive and inferential statistics. The descriptive statistics were expressed in terms of mean±1 SD. The Student t-test and z-test were applied to compare the mean ferritin levels at the start and end of the study period.


  Results Top


[Table 1] shows that the combination therapy group had a higher mean age (P<0.001) compared with the other three groups. Moreover, the patients of the deferasirox group underwent their first blood transfusion at a younger age (P=0.0003).
Table 1: Characteristics of the participating groups

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Three (25%) patients of the DFO group and two (11.1%) of the DFP group had positive hepatitis C virus (HCV) antibodies, whereas none were positive for the hepatitis B virus (HBV) surface antigen. Significantly elevated AST enzyme levels were found in patients of the DFO group (P=0.001) [Table 2]. The difference in the initial and final serum ferritin levels between the four groups was statically insignificant. A significant reduction in serum ferritin levels after 1 year of chelation was detected in all groups (P<0.001) [Table 3]. The reduction in mean serum ferritin levels was more in patients on combination therapy of DFO and DFP compared with the other monotherapy groups (the mean serum ferritin changed from 4202 to 2405 as calculated by the z-test to detect the difference between the means in each group). The percentage of reduction was 42.76% in the combination group, 36.19% in the deferasirox group, 21.22% in the DFP group, and 20.4% in the DFO group [Figure 1].
Figure 1: Changes in the mean serum ferritin levels in the four groups after the 1-year study period.

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Table 2: Laboratory investigations of the participating groups

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Table 3: Statistical comparisons between the mean serum ferritin levels before and after the treatment

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The compliance was bad in two patients on DFO, and they were excluded from the study as they did not receive DFO on a regular basis. Four (22.2%) patients developed elevated liver transaminases, and six (33.3%) patients developed mild bone pain and arthralgia during treatment with oral DFP but did not stop the treatment. However, none of the patients developed neutropenia/agranulocytosis or significant gastrointestinal tract (GIT) symptoms. There were no detectable side effects with the use of deferasirox, except for some GIT pain that improved with continued treatment.


  Discussion Top


RBC transfusion therapy is life saving in thalassemia; obligatory iron loading accompanies such treatment, and chelation therapy to remove and detoxify the iron accumulation resulting from these chronic transfusions must therefore be administered 5.

In thalassemia major, chelation therapy is usually initiated in children of an age of 2 years or older who have received 10 U of RBCs and/or have a serum ferritin level of above 1000 ng/ml on at least two measurements (not obtained when ill). This level of iron overload typically occurs after 1 or 2 years of transfusions 18. Ideally, chelation should be administered in a way so as to prevent excess iron accumulation and the resulting hepatic, endocrinological, and cardiac complications by matching the ongoing transfusional iron intake 5.

Many different studies have been carried out to determine the efficacy of iron-chelating agents in thalassemia. These studies used different parameters like serum ferritin, liver iron concentration by biopsy, and MRI; moreover, some studies also checked for the presence of cardiac siderosis. In this study, it was not possible for us to perform a liver biopsy or MRI because of economic reasons; therefore, we used only serum ferritin as a variable to determine the efficacy of different chelation therapies. This study was the first study to be carried out at our hospital to compare the efficacy of different iron chelation therapies in thalassemic children attending the hematology clinic.

In this study, 12 thalassemic children were selected to receive combination therapy of DFO and DFP; they were already on DFO yet had high serum ferritin levels before the study. They were significantly older compared with the patients on other chelation therapies (P<0.001); moreover, this group had a significantly higher rate of blood transfusion (P=0.02) compared with other groups hence they were more susceptible to complications of iron overload due to more frequent blood transfusions.

In this study, we found an insignificant difference between the four groups as regards most of the laboratory investigations that were carried out as part of their follow-up investigations, except for significantly elevated AST enzyme levels in patients who were on DFO (P=0.001), and this could be explained by the fact that 25% of the patients in this group were positive for HCV antibodies.

There was no statistically significant difference in the initial serum ferritin levels between the four groups. (P=0.05, [Table 2]. The follow-up of the four groups after 1 year showed a significant reduction in their serum ferritin levels in response to chelation therapy (P<0.001) [Table 3]. Our results were in agreement with those of the study by El-Beshlawy et al. 19, which reflected the Egyptian experience on iron chelation and detected a significant reduction in liver iron concentration and serum ferritin levels in all three forms of therapies used for chelation (DFO, DFP, and combined therapy of both); however, a significant reduction in the liver iron score was observed only in the patients on combination therapy, but the cardiac function did not significantly change in any form of therapy.

Sajid et al. 20 reported a good efficacy of DFP in lowering patients’ serum ferritin levels, with low frequency of adverse reactions. Another study by Maggio et al. 21 stated that both DFO and DFP caused a similar reduction in serum ferritin levels over 1 year in patients with relatively low serum ferritin levels before the treatment. In addition, Roberts et al. 22 studied the effect of oral DFP on iron chelation in individuals with thalassemia and suggested that DFP is not an alternative to DFO and should be used in conjunction with DFO for a more effective iron chelation therapy. Extensive long-term experience has shown that combined chelation with DFP and DFO rapidly reduces liver iron and serum ferritin levels as well as myocardial siderosis, improves the cardiac function, reverses and prevents endocrine complications, and reduces cardiac mortality and improves survival 6.

A study on the long-term use of deferasirox in pediatric and adult patients with β-thalassemia suggested that a treatment for 5 years or less is generally well tolerated and effectively reduces the iron burden 23. Moreover, Meerpohl et al. 24 concluded in their review that deferasirox offers an important alternative line of treatment for individuals with thalassemia and secondary iron overload. In our study, side effects with different forms of chelation were reported. In the DFO group, the complications were erythema and pain at the infusion site; moreover, the compliance was an important problem we faced with patients of the DFO group, as two patients showed poor compliance to DFO and were excluded from the final results of the study. Other groups showed good compliance with the chelation therapy. Four patients (22.2%) from the DFP group developed elevated levels of liver transaminases, but this elevation was mild and transient and did not necessitate stopping treatment with oral DFP. None of the patients treated with DFP showed neutropenia/agranulocytosis.

Side effects were observed in a study carried out by Maggio et al. 21, in which the treatment was discontinued because of reversible side effects in five patients in the DFP group (three with hypertransaminasemia and two with leukocytopenia) but none in the DFO group. In another study carried out by Panigrahi et al. 25, the transaminases levels were above the normal upper limits in most of the patients on DFP, and they explained this by the high iron load, as 50% of the patients had high AST and alanine aminotransferase levels before the start of chelation therapy. This may be due to a transfusion-transmitted HCV or HBV infection, as a significant number of patients were positive for HBV and HCV 25.

In the study by El-Beshlawy et al. 19, the compliance improved in patients who received combined therapy, and this was in accordance with our results.

In our study, six patients (33.33%) from the DFP group developed mild bone pain and arthralgia, but this did not necessitate stoppage of treatment and administration of an analgesic for a short duration solved the problem. None of our studied patients under DFP or deferasirox therapy developed neutropenia or any GIT symptoms.

In other studies, such as those of Panigrahi et al. 25, arthropathy and cytopenia were reported. Gastrointestinal symptoms were reported to be the most common symptoms associated with DFP therapy, followed by joint problems, in 15% of the patients, over a period of 4 years 26.


  Conclusion and recommendations Top


It was concluded from this study that DFO, oral DFP, deferasirox, and combined DFO with DFP are effective in reducing serum ferritin levels in thalassemic children. Combination therapy is more effective, with more compliance and less side effects compared with combination therapy. It would be appropriate to study the effect of combined DFO and deferasirox and on a larger number of patients.[26]

 
  References Top

1.Weatherall DJ, Clegg JB The thalassemia syndromes. 20014th ed. Oxford, England Blackwell Science  Back to cited text no. 1
    
2.Olivieri NF, Nathan DG, MacMillan JH, Wayne AS, Liu PP, McGee A, et al. Survival in medically treated patients with homozygous beta-thalassemia. N Engl J Med. 1994;331:574–578  Back to cited text no. 2
    
3.Cunningham MJ. Update on thalassemia: clinical care and complications. Hematol Oncol Clin North Am. 2010;24:215–227  Back to cited text no. 3
    
4.Berdoukas V, Farmaki K, Carson S, Wood J, Coates T. Treating thalassemia major-related iron overload: the role of deferiprone. J Blood Med. 2012;3:119–129  Back to cited text no. 4
    
5.Kwiatkowski JL. Real-world use of iron chelators. Strategies for optimal management of thalassemia now and in the future. Am Soc Hematol. 2011:451–458  Back to cited text no. 5
    
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8.Matsui D, Klein J, Hermann C, Grunau V, McClelland R, Chung D, et al. Relationship between the pharmacokinetics and iron excretion pharmacodynamics of the new oral iron chelator 1, 2-dimethyl-3-hydroxypyrid-4-one in patients with thalassemia. Clin Pharmacol Ther. 1991;50:294–298  Back to cited text no. 8
    
9.Kontoghiorghes GJ, Goddard JG, Bartlett AN, Sheppard L. Pharmacokinetic studies in human with the oral iron chelator 1, 2-dimethyl-3-hydroxypyrid-4-one. Clin Pharmacol Ther. 1990;48:255–261  Back to cited text no. 9
    
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11.Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassemia. Blood. 1997;89:739–761  Back to cited text no. 11
    
12.Agarwal MB, Gupte SS, Viswanathan C, Vasandani D, Ramanathan J, Desai N, et al. Long-term assessment of efficacy and safety of L1, an oral iron chelator, in transfusion dependent thalassemia: Indian trial. Br J Haematol. 1992;82:460–466  Back to cited text no. 12
    
13.Olivieri NF, Brittenham GM, Matsui D, Berkovitch M, Blendis LM, Cameron RG, et al. Iron chelation therapy with oral deferiprone in patients with thalassemia major. N Engl J Med. 1995;332:918–922  Back to cited text no. 13
    
14.Olivieri NF, Sher GD, McKinnon JA, Pope E, Entsuah B, Snider M, et al. The first prospective randomized trial of subcutaneous deferoxamine and the orally active iron chelating agent L1 [abstract]. Blood. 1994;S 84:1436  Back to cited text no. 14
    
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19.El-Beshlawy A, Manz C, Naja M, Eltagui M, Tarabishi C, Youssry I, et al. Iron chelation in thalassemia: combined or monotherapy? The Egyptian experience. Ann Hematol. 2008;87:545–550  Back to cited text no. 19
    
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21.Maggio A, D’Amico G, Morabito A, Capra M, Ciaccio C, Cianciulli P, et al. Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial. Blood Cells Mol Dis. 2002;28:196–208  Back to cited text no. 21
    
22.Roberts DJ, Brunskill SJ, Doree C, Williams S, Howard J, Hyde CJ. Oral deferiprone for iron chelation in people with thalassemia. Cochrane Database Syst Rev. 2007;3:CD 004839  Back to cited text no. 22
    
23.Cappellini MD, Bejaoui M, Agaoglu L, Canatan D, Capra M, Cohen A, et al. Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years’ follow-up. Blood. 2011;118:884–893  Back to cited text no. 23
    
24.Meerpohl JJ, Antes G, Rücker G, Fleeman N, Motschall E, Niemeyer CM, Bassler D.. Deferasirox for managing transfusional iron overload in people with thalassaemia. Cochrane Database Syst Rev. 2012;2:CD007476. doi: 10.1002/14651858.CD007476.pub2  Back to cited text no. 24
    
25.Panigrahi I, Marwaha RK, Das RR. Long-term response to deferiprone therapy in Asian Indians. Ann Hematol. 2010;89:135–140  Back to cited text no. 25
    
26.Cohen AR, Galanello R, Piga A, De Sanctis V, Tricta F. Safety and effectiveness of long term therapy with the oral iron chelator deferiprone. Blood. 2003;102:1583–1587  Back to cited text no. 26
    


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