Iron chelation therapy in the myelodysplastic syndromes and aplastic anemia: a review of experience in South Korea

In order to adequately manage iron overload, it is important that body iron levels are assessed on an ongoing basis. There are a range of techniques available to assess iron levels, including measurement of serum ferritin levels, liver iron concentration (LIC) by biopsy, and the use of magnetic resonance imaging (MRI) to measure hepatic and cardiac iron concentrations [23, 24]. Serum ferritin is the least costly and most convenient and practical of these, and is commonly used in Korea. Levels should be monitored regularly in patients with BMFS who are chronically transfused. Serum ferritin levels <1,000 ng/mL are known to be associated with a very low incidence of iron-induced complications, while patients whose levels are >1,000 ng/mL can suffer from cardiac, hepatic, and endocrine complications of iron overload [14, 25]. LIC is a good predictor of total body iron, and can be measured by direct biochemical measurement using a needle biopsy; however, it can lead to complications such as bleeding, infection, and hemobilia in patients with MDS [26]. MRI indirectly measures iron content using parameters known as T2* or R2*, which are related to the concentration of paramagnetic iron in the organ [26]. A Korean multicenter study on the use of MRI to monitor patients with iron overload is currently ongoing.

To prevent the life-threatening clinical consequences of iron overload, iron chelation therapy should be initiated in chronically transfused patients when serum ferritin levels reach >1,000 ng/mL [14, 27]. From 1998 until recently, DFO was the only iron chelator available in Korea. In many parts of the world, including Korea, DFO is administered as an intravenous (IV) or subcutaneous (SC) infusion over 8–24 h per day, 5–7 days/week. In Korea, some patients receive a concomitant DFO injection during their RBC transfusions. In Japan, it is common practice to administer DFO fortnightly rather than nightly, and in some patients as a bolus IV injection. Moreover, most patients in Japan receive treatment on an outpatient basis, and infusion pumps for DFO therapy are not reimbursed [14].

Although published data on the use of iron chelation therapy are mostly from patients with thalassemia, data in patients with BMFS are emerging. Recent reports from Europe and Canada have shown a survival advantage in transfusion-dependent patients with MDS who were adequately chelated compared with those who were not [28, 29]. Other studies have found that DFO may reduce the transfusion requirement of patients with MDS [30, 31], while another study in 11 patients with MDS demonstrated an improvement in erythropoietic output and a reduction in transfusion requirement following DFO treatment [32]. A third study in 12 multiply transfused patients with various BMFS demonstrated induction of urinary iron excretion and reduction in serum ferritin, liver enzyme and liver iron levels [33]. A further study in six of the same patients with elevated myocardial iron showed normalization of myocardial iron, as estimated by MRI R2* measurements after 6–18 months of treatment with DFO [34].

In Korea, chelation therapy is not widely used for the treatment of patients with iron overload. DFO is usually prescribed only to patients with overt secondary hemochromatosis, and is not routinely used for the prevention of hemochromatosis. The cross-sectional survey conducted by the Korean iron overload study group showed that only 18% of iron-overloaded patients in Korea received iron chelation therapy [13]. Furthermore, iron-overloaded patients with AA are more commonly administered iron chelation therapy than those with MDS. The reluctance to administer iron chelation therapy to patients with MDS in Korea may stem from the advanced age of these patients, and because some patients with poor prognosis may not survive long enough to develop iron overload or to gain benefit from iron chelation therapy. Considerations with administering DFO include the difficulty in obtaining the required infusion pumps and the need for hospitalization. Furthermore, DFO infusions can also have a negative impact on patients’ QoL, as the infusions can be troublesome, time-consuming and painful for patients. This can be particularly problematic in older patients as bruising may occur at the infusion site due to decreased platelet counts or platelet dysfunction [35].

The most common adverse events (AEs) reported following DFO administration are site soreness/rash, allergic reaction to medication, breathing problems, nausea, tinnitus and joint or muscle pain, headache, hives, nausea, fever, vomiting, and abdominal pain [36, 37]. In countries where DFO is administered as an IV or SC infusion, some of these issues can be addressed to some extent to help increase compliance. For example, the injection site of the therapy can be varied to decrease the likelihood of local skin reactions, butterfly needles can be used, and patients should be properly trained to ensure that SC, rather than intradermal, infusions are achieved; patients should also be educated about the most common AEs that might be expected [38]. Specific AEs in patients with BMFS treated with DFO have been noted. Four cases of development of mucormycosis were reported in Japanese patients with AA treated with DFO, indicating that DFO may be a risk factor for mucormycosis in these patients [39]. Furthermore, a case of ocular toxicity was reported in an 8-year-old patient with AA being treated with DFO in Germany for transfusional iron overload. The ocular toxicity improved following discontinuation of DFO for 3 months [40].

Advances in the understanding of the dangers of iron overload and the availability of alternative iron chelation therapies for the management of iron overload may initiate a change in the treatment strategy for iron-overloaded patients with BMFS in Korea. Deferasirox (Exjade^®; ICL670) is a once-daily, oral iron chelator that was launched in Korea in April 2007 for the treatment of transfusional iron overload in pediatric and adult patients [41], and is also approved in the USA, Europe, and many countries worldwide.

During its clinical evaluation around the world, deferasirox was studied in more than 450 patients with MDS and other BMFS [35]. Baseline data from these trials indicated a high iron burden in transfusion-dependent patients with MDS, DBA, AA, and Fanconi’s anemia, suggesting that, despite the prior availability of DFO, these patients had significantly high levels of iron overload [35, 42, 43]. The Catholic University of Korea took part in a 1-year, multicenter study that enrolled patients aged ≥2 years with a range of transfusion-dependent anemias, including MDS. This study demonstrated that patients had a high baseline serum ferritin of 2,755 ng/mL and LIC of 9.4 mg Fe/g dry weight, indicating significant iron burden. For the patients who had previously been chelated, this indicates that their treatment regimen was not providing adequate management of their iron burden, and data clearly indicate a need for chelation therapy in those who were chelation-naïve.

One of the deferasirox core 1-year registration studies in the US included 47 regularly transfused patients with MDS and 30 with DBA, assigned to deferasirox dose groups according to their baseline LIC. This study demonstrated dose-dependent iron excretion in patients with MDS and DBA dosed with deferasirox at 10, 20, and 30 mg/kg/day (Fig. 3), and a statistically significant mean decrease in LIC of 9.9 mg Fe/g dw (±5.5; P < 0.001) in patients receiving 20 or 30 mg/kg/day. The study showed no evidence of differences in the toxicity or tolerability between the patients with MDS and other patients in this trial [35].

In another 3-year prospective deferasirox study in the US enrolling 176 patients with MDS, deferasirox decreased serum ferritin levels from a baseline of 3,398 ± 3,088 to 3,065 ± 1,743, 2,775 ± 1,355, 2,759 ± 1,562, and 2,603 ± 1,336 ng/mL at 3, 6, 9, and 12 months, respectively. There was also a sustained suppression of mean labile plasma iron to the normal range after 3 months of treatment, and a hematological improvement in five (6%) of the patients, as defined by International Working Group criteria: three patients showed an erythroid response (one major; two minor); two major platelet responses and one major neutrophil response [44].

All these trials have shown that deferasirox is generally well tolerated with a defined safety profile in patients with MDS, as well as other anemias. The most common treatment-related AEs included transient, mild-to-moderate gastrointestinal disturbances and skin rash. No progressive increases in serum creatinine were noted [45]. Treatment with deferasirox should be initiated in patients who have received more than 20 units of RBCs and have a serum ferritin level >1,000 ng/mL. The recommended initial daily dose of deferasirox is 20 mg/kg body weight, which can be increased or decreased according to transfusional iron intake, severity of iron overload and the therapeutic goal of the patient, whether to maintain or decrease iron burden [46]. Dose may be adjusted in response to rising serum ferritin levels or emerging AEs. Dose should be increase to 30 mg/kg when there is a 25% increase in serum ferritin levels at two consecutive examinations. In the case of AEs, dose should be reduced by 10 mg/kg if there is a rise in serum creatinine of >50% from baseline, especially in patients who are receiving concomitant cyclosporine A. Dose should similarly be reduced in patients who experience dyspepsia, nausea, vomiting, epigastric pain, and diarrhea.

The most common AEs noted from deferasirox administration are mild-to-moderate gastrointestinal disturbances (Table 3). Diarrhea can be treated with loperamide in the first instance; if it is not controlled, dose should be reduced by half. If diarrhea continues to persist, the medication should be taken before bedtime rather than in the morning. After the diarrhea has resolved, the patients may be rechallenged at a lower dose of deferasirox, gradually escalated to a full dose. Mild-to-moderate rash often resolves spontaneously, and deferasirox may be continued without dose adjustment. Severe skin rash can be treated by discontinuing deferasirox and initiating prednisolone. After the rash has resolved, the patients can be rechallenged with a half dose deferasirox, with or without low-dose prednisolone, and gradually escalated to a full dose. AEs in pediatric patients should be managed in the same way as adult patients. In patients undergoing treatment with immunosuppressive therapies, deferasirox can be administered concomitantly alongside cyclosporine A. In those with iron overload who are candidates for HSCT, deferasirox can be administered prior to HSCT to reduce the patients’ iron burden.