Korean Guideline for Iron Chelation Therapy in Transfusion-Induced Iron Overload



# Introduction
Regular red blood cell (RBC) transfusions are the major supportive care for many Korean patients with aplastic anemia (AA), myelodysplastic syndromes (MDS), or other rare anemias. Physicians most commonly use the hemoglobin (Hgb) level to determine whether or not to transfuse [bib_ref] Red blood cell transfusion practice in elective orthopedic surgery: a multicenter cohort..., Vuille-Lessard [/bib_ref]. However, most guidelines recommend that transfusions should be given for symptoms of anemia and that the decision to transfuse should not be based on the Hgb level alone [bib_ref] Clinical practice guideline: red blood cell transfusion in adult trauma and critical..., Napolitano [/bib_ref].
An optimal RBC transfusion regimen involves administering sufficient RBCs to maximize clinical benefits while avoiding unnecessary transfusions that increase costs and expose patients to potential risks, including infection and iron overload. Hence, the Korean Society of Blood Transfusion (KSBT) recommends transfusion to be considered at Hgb concentrations of 7 g/dL or less in chronically anemic patients. KSBT does not rec-ommend routine RBC transfusion when Hgb > 7 g/dL. Furthermore, KSBT only recommends RBC transfusion in those patients with symptoms such as dyspnea, palpitation on exertion, or edema.
Chronic transfusion therapy inevitably leads to secondary iron overload, which can cause significant damage to many organs such as the liver, heart, and endocrine system. Recently, deferasirox (DFX), an oral iron chelator, has been introduced and has been shown to improve the treatment of iron overload [bib_ref] Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC..., Cappellini [/bib_ref]. To summarize the evidence and provide practical guidelines for iron chelation in Korea, the Korean Society of Hematology Aplastic Anemia Working Party (KSHAAWP) describes here general considerations regarding iron overload in transfusion dependent patients and proposes guidelines for the treatment of iron overload based on published clinical evidence and the experience of the expert panel.

## Pathophysiology of iron overload
Iron metabolism and the mechanism of organ damage Iron is involved in many critical steps of cellular metabolism such as cellular respiration, heme synthesis, production of oxygen radicals, antioxidation, and DNA synthesis and repair, as well as in cellular proliferation and inflammation. Normal body iron stores are 3-4 g; an excess of iron of 20 g or more can lead to organ damage [bib_ref] Practical management of iron overload, Porter [/bib_ref]. Most additional iron can be stored within the reticuloendothelial system (RES). However, if the iron level exceeds the capacity of the RES to retain it, the excess iron will be released into the plasma. Normally, transferrin binds this released iron but, if the plasma iron concentration continues to rise, transferrin saturation may result. This scenario may occur with sequential transfusions: when the RES cannot retain all of the iron, it then diffuses into the plasma in amounts that exceed the capacity of transferrin to bind it. As a result, non-transferrin-bound iron, which seems to be the major mediator of extrahepatic tissue damage in transfusional iron overload, appears in the plasma [bib_ref] Impact of transfusion dependency and secondary iron overload on the survival of..., Malcovati [/bib_ref]. The harmful effects of excess iron may result from deposition into tissues and organs, but also from oxidative stress. Non-transferrin-bound plasma iron is deposited specifically in tissues with high level of transferrin receptors (eg, liver, heart, anterior pituitary, and pancreas). As the human body has no mechanism for excreting excess iron, and each unit of transfused RBCs contains 200-250 mg of iron, iron overload can readily occur in patients given multiple transfusions, typically after 10 to 20 transfusions (6). In the absence of treatment to reduce iron overload, progressive cardiomyopathy, cirrhosis, endocrinopathy and diabetes can have a serious impact on morbidity and mortality. Iron chelation therapy in patients given multiple transfusions aims to prevent or reverse some of these consequences and has been associated with a reduced morbidity and mortality [bib_ref] Improvement in iron status and liver function in patients with transfusional iron..., Hoffbrand [/bib_ref].

## Measuring and monitoring body iron
Serum ferritin is the most common indirect parameter used to assess body iron stores in the clinical setting. Measurement of serum ferritin is easy and inexpensive but individual values may be affected by infection, inflammation, liver disease, vitamin C deficiency, and hemolysis [bib_ref] Serum ferritin, liver iron stores, and liver histology in children with thalassaemia, Virgiliis [/bib_ref]. Although ferritin is not the most accurate marker of iron overload, ferritin levels do correlate with transfusion burden [bib_ref] Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO..., Malcovati [/bib_ref] and liver iron concentration (LIC) [bib_ref] Serum ferritin, liver iron stores, and liver histology in children with thalassaemia, Virgiliis [/bib_ref] , and trends in ferritin levels are useful for following iron load.
Liver biopsy is considered the gold standard for direct measurement of total body iron, but the use of this invasive technique is excluded in many patients because of thrombocytopenia and neutropenia, which may predispose to bleeding and infectious complications [bib_ref] Monitoring chelation therapy to achieve optimal outcome in the treatment of thalassaemia, Porter [/bib_ref].
Non-invasive measurement techniques are being developed, including T2* MRI and magnetic susceptometry using a superconducting quantum interference device (SQUID). These techniques have been shown in some studies to provide results that correlate well with liver biopsy-determined iron concentrations [bib_ref] Iron-chelating therapy and the treatment of thalassemia, Olivieri [/bib_ref] [bib_ref] Magnetic-susceptibility measurement of human iron stores, Brittenham [/bib_ref] [bib_ref] Assessment of iron distribution between liver, spleen, pancreas, bone marrow, and myocardium..., Papakonstantinou [/bib_ref] , but they are not widely available worldwide. The data reported in a recent study indicate that serial measurements of serum ferritin are useful for monitoring chelation therapy with DFX so that doses may be adjusted according to the ongoing iron load due to transfusion [bib_ref] Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC..., Cappellini [/bib_ref]. The DFX prescribing information recommends monitoring serum ferritin monthly to assess the patient's response to therapy and adjusting the DFX dose, if necessary, every 3 to 6 months (16).

## Clinically available iron chelators
Currently, three chelating agents are available: deferoxamine, deferiprone, and DFX.

## Deferoxamine (desferal tm )
Deferoxamine (DFO) has been in widespread clinical use since the late 1970s and has provided unequivocal evidence that effective chelation therapy can arrest the progression of, and prevent early death from, iron overload [bib_ref] Intensive iron-chelation therapy with desferrioxamine in iron-loading anaemias, Pippard [/bib_ref]. DFO is a trihydroxamic acid sideraphore secreted by Streptomyces pilosus, a fungus. DFO is a hexadentate chelator with a very high and selective affinity for iron. One molecule of DFO binds one atom of iron. DFO is administered as long parenteral infusions because the plasma half-life is short (min) and it is not active orally. It is usually given as an overnight subcutaneous infusion 5 to 7 nights per week. It is mainly distributed extracellularly and the protein binding in plasma is low (< 10%). After complexing with iron it is excreted rapidly as ferrioxamine, mainly through the kidney and one-third into bile through the feces. Thus, its efficacy is also dependent upon adequate urine output and may be facilitated by dialysis in the case of kidney dysfunction. This requirement is extremely demanding and can result in poor adherence, thereby compromising efficacy and outcomes [bib_ref] Iron chelation therapy, Hershko [/bib_ref].

## Deferiprone (ferriprox tm )
Deferiprone (L1; CP20; 1,2-dimethyl-3-hydroxypyrid-4-one) is an orally active hydroxypyridineone first used in humans in 1987. Deferiprone is a bidentate chelator. Three molecules of deferiprone are needed to bind one atom of iron. An advantage of this compound is that the iron chelate of deferiprone carries no net charge and, therefore, can penetrate membranes easily, allowing removal of potentially toxic iron from tissues [bib_ref] The design of orally active iron chelators, Hider [/bib_ref]. Other major advantages include oral administration and rapid absorption through the gastrointestinal tract. Deferiprone is mainly metabolized as glucuronide conjugates and is excreted via the renal route. It has a half-life of 2-3 hr. The typical dosage of deferiprone is 75 mg/kg/day in 3 divided doses, up to 100 mg/ http://dx.doi.org/10.3346/jkms.2013. kg daily [bib_ref] Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with..., Pennell [/bib_ref] [bib_ref] Safety and effectiveness of 100 mg/kg/day deferiprone in patients with thalassemia major:..., Taher [/bib_ref]. Deferiprone is rapidly absorbed mainly from the stomach and reaches the circulation quickly. However, there may possibly be food-drug interactions or other gastric factors that delay the appearance of the drug in the blood following oral administration. Wide variations in the metabolism and clearance of deferiprone among patients have been observed, mainly depending on the iron overload and availability of chelatable iron [bib_ref] Oral iron chelators, Cappellini [/bib_ref]. This agent is approved in some Asian and European countries for second-line treatment of iron overload, but not in the USA and Canada due to its narrow therapeutic index and safety concerns including a risk of agranulocytosis [bib_ref] Efficacy and safety of deferiprone (Ferriprox), an oral iron-chelating agent, in pediatric..., Won [/bib_ref] [bib_ref] The safety and effectiveness of deferiprone in a large-scale, 3-year study in..., Ceci [/bib_ref].

## Deferasirox (exjade tm )
DFX (ICL670) is a new oral tridentate iron (Fe 3+ ) chelator developed specifically for the treatment of chronic iron overload. It is an N-substituted bis-hydroxyphenyl-triazole selected from more than 700 compounds screened as part of a national drug development program [bib_ref] Development of tridentate iron chelators: from desferrithiocin to ICL-670, Nick [/bib_ref]. Two molecules of DFX are needed to bind one atom of iron. With a plasma half-life of 8 to 16 hr, oncedaily dosing permits circulating drug to continuously scavenge non-transferrin-bound "labile plasma iron, " which is the chemical species responsible for generating toxic oxygen intermediaries that can cause tissue damage in iron-overloaded subjects [bib_ref] Role of iron in inducing oxidative stress in thalassemia: can it be..., Rachmilewitz [/bib_ref]. Hepatocytes readily take up DFX, which chelates hepatocellular iron. The DFX-iron complex is then excreted in the bile [bib_ref] Pharmacokinetics, metabolism, and disposition of deferasirox in beta-thalassemic patients with transfusion-dependent iron..., Waldmeier [/bib_ref]. Within cells, DFX chelates cytosolic iron, leading to ferritin degradation by the proteasome [bib_ref] Specific iron chelators determine the route of ferritin degradation, De Domenico [/bib_ref].

## Clinical benefits
Iron chelation therapy has been shown to be beneficial in patients with transfusion-dependent anemia, especially -thalassemia major. One small, randomized trial and many other observational studies have demonstrated that maintenance of low serum ferritin levels using iron chelators was associated with a reduction in end-organ toxicity as well as prolongation of survival in patients with transfusion-dependent anemia [bib_ref] Update on iron chelators in thalassemia, Neufeld [/bib_ref] [bib_ref] Iron-chelating therapy for transfusional iron overload, Brittenham [/bib_ref]. In Korea, thalassemia is very rare and major indication for iron chelation therapy includes AA and MDS [bib_ref] Iron chelation therapy in the myelodysplastic syndromes and aplastic anemia: a review..., Lee [/bib_ref]. Guidelines for the management of AA or MDS suggest that iron chelation therapy should be considered for the patients with iron overload, although the guidelines often differ in specific details [bib_ref] Guidelines for the diagnosis and management of aplastic anaemia, Marsh [/bib_ref] [bib_ref] Iron chelation therapy in MDS: what have we learnt recently?, Schmid [/bib_ref].
Few studies have assessed the efficacy of iron chelation therapy in patients with AA. The prospective 1-yr Evaluation of Patients' Iron Chelation with DFX (EPIC) study enrolled the largest number (n = 116) of AA patients and showed the effectiveness of DFX in reducing body iron (4). However, no trial has established the long-term effectiveness of iron chelation therapy in preventing organ toxicity or improving survival in patients with AA.
Clinical effects of iron chelation therapy in iron overloaded patients with MDS have been studied in several aspects: survival prolongation, improvement of organ function, improved outcomes after allogeneic hematopoietic stem cell transplantation (HSCT), and cytopenia improvement in lower risk MDS. However, these potential benefits of iron chelation therapy in MDS patients remain controversial [bib_ref] Controversies surrounding iron chelation therapy for MDS, Leitch [/bib_ref]. For example, iron chelation therapy may not be beneficial in patients with MDS whose expected survival is less than one year. In individual patients receiving long-term transfusion, the benefits of iron chelation therapy may vary according to the morbidity associated with the therapy, the estimated prognosis of MDS, and the latency period between the onset of transfusion and the development of clinical manifestations of iron overload [bib_ref] Iron-chelating therapy for transfusional iron overload, Brittenham [/bib_ref].
Recent retrospective data suggest that efficient iron chelation therapy may prolong survival in patients with MDS [bib_ref] Does iron chelation therapy improve survival in regularly transfused lower risk MDS..., Rose [/bib_ref] [bib_ref] Improving clinical outcome in patients with myelodysplastic syndrome and iron overload using..., Leitch [/bib_ref]. The Groupe Francophone des Myelodysplasies reported a retrospective study in which 97 patients with low or intermediate-1 IPSS risk presenting for RBC transfusion over a one-month period were analyzed, and 53 patients (55%) received iron chelation therapy for at least 6 months. Median survival was 124 months in the group of patients receiving standard or adequate chelation (n = 41, deferoxamine by infusion at least 3 days per week, or deferiprone, deferasirox, or a combination of agents) compared to 85 months in those receiving low or weak chelation (n = 12; deferoxamine by intermittent bolus) and 53 months in non-chelated patients (n = 44) (P < 0.01) [bib_ref] Does iron chelation therapy improve survival in regularly transfused lower risk MDS..., Rose [/bib_ref]. In a retrospective study from Vancouver, the four year survival was 80% for chelated patients with low or intermediate-1 IPSS risk MDS and it was 44% for non-chelated patients (P < 0.03) [bib_ref] Improving clinical outcome in patients with myelodysplastic syndrome and iron overload using..., Leitch [/bib_ref]. So far, there have been no randomized trials examining whether morbidity or mortality would be improved with iron chelation therapy in patients with MDS. One randomized trial is currently recruiting patients to prospectively assess the efficacy and safety of iron chelation therapy with DFX compared to placebo in MDS patients with transfusional iron overload.
Although iron chelation therapy is well established to reverse hepatic or cardiac dysfunction and reduce the risk of diabetes mellitus in beta-thalassemia major, there have been only limited data for the effects of iron chelation therapy on organ function in MDS. Retrospective nationwide survey of Japanese patients with transfusion-dependent MDS and AA showed that effective chelation with deferoxamine resulted in improved serum ferritin, liver enzymes, and fasting blood sugar [bib_ref] Iron-chelating therapy and the treatment of thalassemia, Olivieri [/bib_ref] [bib_ref] Long-term outcome of continuous 24-hour deferoxamine infusion via indwelling intravenous catheters in..., Davis [/bib_ref] [bib_ref] Retrospective nationwide survey of Japanese patients with transfusion-dependent MDS and aplastic anemia..., Takatoku [/bib_ref]. The EPIC study enrolled 341 patients with MDS and overall median serum ferritin decreased significantly at 1 yr (P = 0.002). Alanine aminotransferase levels also decreased significantly and the change correlated significantly with reduction in serum ferritin (P < 0.001) [bib_ref] Deferasirox in ironoverloaded patients with transfusion-dependent myelodysplastic syndromes: results from the large..., Gattermann [/bib_ref].
In higher risk MDS, unlikely the case with lower risk MDS who would live long enough to experience adverse effects of http://dx.doi.org/10.3346/jkms.2013.28.11.1563 iron overload-induced tissue damage, the major benefit of iron chelation therapy is not likely to come from reduction in end organ damage due to tissue iron overload, but from potential beneficial effects on other outcomes such as reduction of infections, prevention or delay of leukemic evolution, and improved outcomes after allogeneic HSCT [bib_ref] Objectives of iron chelation therapy in myelodysplastic syndromes: more than meets the..., Pullarkat [/bib_ref]. It has been evidenced that iron overload increases infection risk and iron chelators, especially DFX with in vitro fungicidal effects and long half-life, may lower infection risk in higher risk MDS with neutropenia [bib_ref] Objectives of iron chelation therapy in myelodysplastic syndromes: more than meets the..., Pullarkat [/bib_ref] [bib_ref] Natural resistance, iron and infection: a challenge for clinical medicine, Bullen [/bib_ref]. Excessive labile plasma iron (LPI) in iron overload can lead to increased generation of reactive oxygen species (ROS), which can induce genomic instability in hematopoietic stem cells [bib_ref] Regulation of reactive oxygen species and genomic stability in hematopoietic stem cells, Naka [/bib_ref]. Thus, use of iron chelating agents in higher risk MDS may prevent or delay progression to AML [bib_ref] Objectives of iron chelation therapy in myelodysplastic syndromes: more than meets the..., Pullarkat [/bib_ref]. In a subgroup analysis of 18 patients with low or intermediate-1 risk MDS who were treated with subcutaneous deferoxamine, median leukemia-free survival was not reached at 226 months compared with a matched control group who had a median leukemia-free survival of 40 months [bib_ref] Controversies surrounding iron chelation therapy for MDS, Leitch [/bib_ref].
In the allogeneic HSCT setting, iron overload is known to increase the risk of transplant-related mortality (TRM) and other complications including fungal infections, hepatic dysfunction, and hepatic veno-occlusive disease after HSCT [bib_ref] Iron overload adversely affects outcome of allogeneic hematopoietic cell transplantation, Pullarkat [/bib_ref] [bib_ref] Iron overload might increase transplant-related mortality in haematopoietic stem cell transplantation, Altes [/bib_ref] [bib_ref] Iron overload in bone marrow transplant recipients, Strasser [/bib_ref] [bib_ref] Iron overload manifesting as apparent exacerbation of hepatic graftversus-host disease after allogeneic..., Kamble [/bib_ref]. Until now, the adverse prognostic impacts of iron overload on the transplantation outcomes have been evaluated in the patients with various hematologic disorders including thalassemia, MDS, and acute leukemia [bib_ref] Iron overload adversely affects outcome of allogeneic hematopoietic cell transplantation, Pullarkat [/bib_ref] [bib_ref] Antin JH. Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing..., Armand [/bib_ref] [bib_ref] Red blood cell transfusion dependence and outcome after allogeneic peripheral blood stem..., Platzbecker [/bib_ref] [bib_ref] Effect of iron overload and iron-chelating therapy on allogeneic hematopoietic SCT in..., Lee [/bib_ref]. Therefore, for candidates to allogeneic HSCT, iron chelation therapy seems to be important to reduce TRM and achieve better transplantation outcome.
According to a recent report, iron chelation therapy should be considered in patients with iron overload because it can prevent organ damage by reducing the iron overload and also may improve hematopoiesis [bib_ref] Improvement in hematopoiesis after iron chelation therapy with deferasirox in patients with..., Lee [/bib_ref]. In this study, 4 cases of AA raised the possibility of a potential additive benefit on hematopoiesis following iron chelation therapy with DFX. Possible effect on hematopoiesis is DFX can suppress LPI and ROS and may inhibit apoptosis. Other possible effects of DFX on hematopoiesis include altering intracellular levels of the nuclear transcription factor NF-kB or increasing erythropoietin levels [bib_ref] Controversies surrounding iron chelation therapy for MDS, Leitch [/bib_ref] [bib_ref] Objectives of iron chelation therapy in myelodysplastic syndromes: more than meets the..., Pullarkat [/bib_ref].

## Current status of iron overload and practice in korea
According to a multicenter, cross-sectional survey of 1,128 adult Korean patients with AA or MDS, a substantial proportion (n = 331, 29%) suffered from iron overload (serum ferritin > 1,000 ng/mL), and all of the patients analyzed who were treated with DFO iron chelation therapy experienced organ damage. Interestingly, in these patients, iron chelation treatment was not actively administered until complications related to iron overload had appeared. Among the 331 patients who were diagnosed with iron overload, 97 also had organ dysfunction and they were heavily transfused, with a high iron burden (high serum ferritin level) and a long duration of disease. This study also showed that there was a correlation between serum ferritin and the number of transfusions, duration of transfusion therapy, and duration of transfusion dependence [bib_ref] Iron chelation therapy in the myelodysplastic syndromes and aplastic anemia: a review..., Lee [/bib_ref].
In a retrospective analysis of 101 Korean children receiving HSCT, patients were divided into three groups according to their ferritin levels at the time of transplantation as follows: patients with serum ferritin > 1,000 ng/mL at the time of HSCT, serum ferritin < 1,000 ng/mL before HSCT without iron chelation therapy, and serum ferritin that decreased to < 1,000 ng/ mL after iron chelation therapy before HSCT. In this study, patients with serum ferritin < 1,000 ng/mL before HSCT had higher survival rates and lower treatment-related mortality compared to patients with serum ferritin > 1,000 ng/mL. The authors concluded that iron chelation therapy before HSCT can improve the outcome (50).

## Korean guideline for iron chelation therapy
Iron chelation therapy is critical and there is much evidence of its clinical benefits in patients with transfusion-induced iron overload. To optimize iron chelation therapy, the KSHAAWP has constructed a Korean guideline for the treatment of transfusion-induced iron overload.
Components of the Korean iron chelation guideline are given below.

## Determining patients who need iron chelation therapy
Transfusion-dependent patients (MDS, AA, pure red cell aplasia, myelofibrosis, etc.) need iron chelation therapy. Transfusion-dependent patients are defined as those receiving > 8 RBC units with a serum ferritin level > 1,000 ng/mL in at least two successive tests. Patients should have a life expectancy of more than 1 yr.

## Initiating iron chelation
Oral DFX and deferoxamine are available in Korea. However, due to short half life and poor compliance, deferoxamine is not recommended as a standard treatment for iron overload. Oral DFX is a recommended treatment in Korean patients with iron overload. The recommended initial daily dose of DFX is 20 mg/ kg body weight, taken on an empty stomach at least 30 min before food. Tablets are available in dosages of 125, 250, or 500 mg and should be dispersed in water or orange or apple juice.

## Monitoring and maintenance therapy
After initiating iron chelation therapy, serum ferritin levels and organ functions including cardiac, hepatic and renal functions http://dx.doi.org/10.3346/jkms.2013. should be checked monthly during the first 3 months and then at least once every 3 months. It is recommended that serum ferritin levels be maintained below 1,000 ng/mL and that, when ferritin levels are < 500 ng/mL at two successive tests, iron chelation should be discontinued. If ferritin levels continue to increase after initiating therapy, increase the DFX dose up to 30 mg/kg/day. After discontinuing iron chelation, if serum ferritin levels increase above 1,000 ng/mL, restart DFX at the same dose. This guideline is summarized in .

## Adverse events

## Gastrointestinal disturbances
Safety data for DFX have been reported in many studies for patients with various anemias [bib_ref] Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to..., Porter [/bib_ref] [bib_ref] Patient-reported outcomes of deferasirox (Exjade, ICL670) versus deferoxamine in sickle cell disease..., Vichinsky [/bib_ref] [bib_ref] A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator,..., Cappellini [/bib_ref] [bib_ref] Phase II clinical evaluation of deferasirox, a once-daily oral chelating agent, in..., Galanello [/bib_ref]. In the EPIC study, DFX was well tolerated with a clinically manageable side effect profile [bib_ref] Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC..., Cappellini [/bib_ref]. According to previous studies, the most common drug-related adverse events (AE) were gastrointestinal (GI) disturbances such as abdominal pain (6%), nausea (22%), vomiting (8%), and diarrhea (15%). These events were seen to be generally mildto-moderate in severity and dose dependent, tended to occur early in the course of treatment and usually lasted less than 1 week, and in general, resolved spontaneously without the need for dose adjustment or discontinuation of treatment [bib_ref] Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC..., Cappellini [/bib_ref].

## Expert panel recommendations for gi disturbances
Management of diarrhea requires an exact diagnosis to exclude other etiologies. The expert panel recommends hydration and the use of loperamide for a maximum of 2 days, with evening pre-prandial DFX dosing. The panel does not recommend administration before bedtime because of the risk of esophageal irritation and bleeding. The panel does not recommend DFX dose reduction in cases of mild diarrhea. In cases of persisting moderate-to-severe diarrhea, dose reduction to 10 mg/kg/day should be considered for moderate diarrhea but cease DFX administration for severe diarrhea. When moderate diarrhea has resolved, the DFX dose should be increased in 5 mg/kg/day steps to the target dose. In severe cases, the panel recommends re-initiating the DFX dose at 10 mg/kg/day and adjusting the dose in increments of 5 mg/kg each week to the target dose. These recommendations are summarized in .
In cases of abdominal pain the panel recommends evening pre-prandial dosing and consumption of soft food for several hours after taking DFX. The panel does not recommend the use of narcotic analgesic drugs or non-steroidal anti-inflammatory drugs because of side effects. If patients have persistent mildto-moderate pain, dose reductions should be considered before discontinuation. Reduce the dose in steps of 5 mg/kg/day . Korean guideline for iron overload Determining which patients need iron chelation therapy (all criteria must be satisfied)  Transfusion-dependent patients: MDS, AA, primary red cell aplasia, myelofibrosis, etc.  RBC transfusion  8 units  Ferritin > 1,000 ng/mL  Life expectancy  1 yr Initiating Iron Chelation  Starting dose: deferasirox (DFX) 20 mg/kg/day  If not effective, DFX dose can be increased to 30 mg/kg/day  Take on an empty stomach at least 30 min before food  Tablets are available in dosages of 125, 250, or 500 mg  Disperse in water or orange or apple juice Monitoring and maintenance therapy  Check ferritin levels and organ functions including renal, hepatic function every month for the first 3 months  After 3 months, check ferritin levels and organ functions at 3 month intervals  Maintain the ferritin level at < 1,000 ng/mL  If the ferritin level is < 500 ng/mL, stop iron chelation  After discontinuing of iron chelation, if the ferritin level is > 1,000 ng/mL, restart DFX . Management of adverse events -Diarrhea (reported incidence: 15%).
 Hydration  Loperamide  Pre-prandial evening DFX dosing  Reduce DFX dose to 10 mg/kg/day in moderate diarrhea  Discontinue DFX dose in severe diarrhea

## Diarrhea resolves
 Continue hydration  Re-escalate DFX dose to target dose in increments of 5 mg/kg each week in moderate diarrhea  Re-initiate DFX dose at 10 mg/kg/day and dose adjust in increments of 5 mg/kg each week to target dose in severe diarrhea Diarrhea persists or is worse after treatment  Investigate other reasons for diarrhea  Discontinue DFX therapy if diarrhea is unmanageable on re-initiation http://dx.doi.org/10.3346/jkms.2013. and increment the dose in steps of 5 mg/kg/day after the pain has resolved. If persistent severe abdominal pain occurs, temporarily discontinue DFX treatment and re-initiate and escalate in 5 mg/kg/day steps after the abdominal pain has resolved. These recommendations are summarized in [fig_ref] Figure 2: Management of adverse events -Abdominal pain [/fig_ref].
For the management of nausea and vomiting the expert panel recommends hydration, and preprandial administration of DFX in the evening should be considered. In cases of severe vomiting reduce the DFX dose in steps of 5 mg/kg/day. When the symptoms have resolved, re-initiate DFX and increase the dose in increments up to the target dose. These recommendations are summarized in [fig_ref] Figure 3: Management of adverse events -Nausea/vomiting [/fig_ref].

## Renal adverse events
Some mild increases in serum creatinine levels have been observed and these appear to be dose dependent. In patients with -thalassemia, 3% overall had serum creatinine values that increased more than 33% above baseline but were still within the normal range [bib_ref] Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised,..., Nisbet-Brown [/bib_ref]. In patients with AA, 25% experienced an increase in serum creatinine to more than 33% above baseline and higher than the upper limit of normal (ULN) on two consecutive visits, but there were no progressive increases. The only factor identified as having a significant impact on serum creatinine was concomitant use of the immunosuppressive agent cyclosporine, a drug with a well-recognized potential to Pre-prandial evening DFX dosing  Take soft food for several hours after DFX  Do not recommend DFX before bedtime  Do not use narcotic pain medications or non-steroidal anti-inflammatory drugs  Consider dose reduction in step of 5 mg/kg/day before discontinuation in mild-to-moderate cases  Temporarily discontinue DFX in severe cases Abdominal pain resolves  Continue DFX  Re-escalate DFX dose to target dose in increments of 5 mg/kg each week in moderate abdominal pain  Re-initiate DFX dose at 10 mg/kg/day and dose adjust in increments of 5 mg/kg each week to target dose in severe abdominal pain Abdominal pain persists or is worse after treatment  Investigate other reasons for abdominal pain  Reduce DFX dose in steps of 5 mg/kg/day before discontinuation in persistent mild-to-moderate abdominal pain  Discontinue DFX therapy if abdominal pain is unmanageable on re-initiation impair renal function. Careful monitoring of renal function is necessary in patients with AA who are receiving concomitant cyclosporine and DFX (4).

## Expert panel recommendations for renal adverse events
The management of serum creatinine increases should be individualized. It is recommended that serum creatinine levels be assessed in duplicate before initiating therapy and monitored monthly thereafter. Patients who have additional renal risk factors, such as preexisting renal or co-morbid conditions, are elderly, or are receiving medicine that depresses renal function should be monitored weekly during the first month after initiation or modification of the DFX dose and monitored monthly thereafter. In patients who exhibit serum creatinine elevations to more than 33% above baseline but still within the normal range at two consecutive visits, the daily dose should be reduced by 10 mg/kg. If there is a progressive increase in serum creatinine beyond ULN, DFX should be discontinued [bib_ref] Clinical application of deferasirox: practical patient management, Vichinsky [/bib_ref]. Once the creatinine level has returned to within the normal range, and if the clinical benefit is expected to exceed the potential risks, DFX should be re-initiated at 10 mg/kg/day and increased in 5 mg/ kg/day steps to the target dose. These recommendations are summarized in [fig_ref] Figure 4: Management of renal adverse events [/fig_ref].

## Hepatic and skin adverse events
In the 1-yr trials, up to 2% of patients developed elevations in serum transaminases. These elevations were not related to dose [bib_ref] Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC..., Cappellini [/bib_ref]. In previous studies, up to 11% of patients developed dosedependent skin eruptions and most symptoms were mild to moderate [bib_ref] Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC..., Cappellini [/bib_ref].

## Expert panel recommendations for hepatic and skin adverse events
As a precaution, liver function should be monitored monthly. Furthermore, following any severe or persistent elevations in serum transaminase levels, dose modification should be considered and a hepatologist should be consulted. Therapy may be restarted in patients once serum transaminase levels have returned to within normal limits and levels should be monitored monthly.
In cases of mild-to-moderate skin adverse events, the expert  If Cr > 33% above baseline but still within normal range at two consecutive visits, DFX should be reduced by 10 mg/kg  Discontinue DFX dose if progressive Cr elevation Creatinine level returns to normal range  Re-escalate DFX dose to target dose in increments of 5 mg/kg each week in case of reduced dosing  Re-initiate DFX dose at 10 mg/kg/day and dose adjust in increments of 5 mg/kg each week to target dose in case of discontinuation Creatinine level progressively increases  Investigate other reasons for renal impairment  Discontinue DFX therapy  Do not reduce dose in mild-to-moderate cases  Temporarily discontinue DFX in severe cases  Short-term use of steroid Skin eruptions resolve  Continue DFX in mild-to-moderate cases  Re-initiate DFX dose at 10 mg/kg/day and dose adjust in increments of 5 mg/kg each week to target dose in case of discontinuation Skin eruptions persist or are worse after treatment  Investigate other reasons for skin eruptions  Discontinue DFX therapy http://dx.doi.org/10.3346/jkms.2013.28.11.1563 panel does not recommend dose reduction because most skin eruptions resolved spontaneously without treatment. But if the skin eruptions persist or are worse after 1 week the panel advises a temporary discontinuation of DFX treatment until the skin eruptions have disappeared. Short-term use of a steroid should be considered. DFX should then be reinitiated and the dose should be escalated in 5 mg/kg/day steps. These recommendations are summarized in [fig_ref] Figure 5: Management of skin adverse events [/fig_ref].

## Other general considerations
Although the increases in adverse events described above have been reported as dose dependent, recent data showed that the safety profile of DFX in patients who received more than 30 mg/ kg/day was consistent with that of patients who received less than 30 mg/kg/day. Interestingly, this study also demonstrated that no adverse events were observed following escalation to over 30 mg/kg/day that were not present at lower doses.
There was a higher incidence of drug-related AEs and higher treatment discontinuation rates in patients with MDS than in patients with other chronic anemias [bib_ref] Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC..., Cappellini [/bib_ref]. This may be related to the risk of disease progression, preexisting co-morbidities, use of concomitant medication, and the advanced ages of patients with MDS.
Most AEs resolved spontaneously and no patients with renal or hepatic failure or drug-related cytopenia have been reported in any of the studies to date. The only contraindication to DFX is prior hypersensitivity to the drug.
DFX has not been investigated in pregnant or breast feeding women, or in pediatric patients younger than 2 yr. Iron chelation should be ceased as soon as pregnancy is confirmed. Caution should be considered in patients older than 65 yr due to a greater frequency of preexisting suppressed hepatic, renal, or cardiac function.

# Conclusion
Iron overload is a major concern in patients with chronic anemia for whom regular transfusions are necessary. Evidence from many clinical trials has demonstrated clear reduction of the iron burden and improvement in organ function after administration of DFX to patients with transfusion-induced iron overload. This guideline could help many Korean physicians to anticipate potential effects, alert patients to the likelihood of key events, and readily provide effective management according to the recommendations outlined.
[fig] Figure 2: Management of adverse events -Abdominal pain (reported incidence: 6%). [/fig]
[fig] Figure 3: Management of adverse events -Nausea/vomiting (reported incidence: 22%, 8%). [/fig]
[fig] Figure 4: Management of renal adverse events (reported incidence: 25%). [/fig]
[fig] Figure 5: Management of skin adverse events (reported incidence: 11%). [/fig]