Management of Oral Iron Chelator Deferasirox for Transfusion-Dependent Patients with Hematological Disorders : 2-Year Experience at a Single Institution in Japan

Introduction: Deferasirox is an oral iron chelator, approved worldwide for the treatment of chronic iron overload due to transfusion. Deferasirox was permitted two years ago in Japan, but there is little known regarding its efficacy and tolerability in clinical practice. Methods: We conducted a retrospective study of 18 patients with transfusion-dependent anemias treated by deferasirox at our institution. The starting dose was individualized and ranged from 6.4 to 26.3 mg/kg/day. Routine clinical laboratory data were followed, and serum ferritin was assessed every 4 weeks. Results: The mean serum ferritin level of 18 patients at the time of deferasirox induction was 3162 ng/ml. 10 of 18 patients could sustain deferasirox treatment for at least 6 months, at an average maintenance dose of 10.8 mg/kg/day. Serum ferritin reduction was observed in 4 patients, at doses less than 20 mg/kg/day. Eighty-nine percent of the patients had adverse events and 13 of them in all ultimately discontinued. Myelodysplastic syndrome (MDS) patients showed poor tolerability. Severe infections of grade 3 or more were documented in 6 patients, and 2 of them were fatal. Conclusions: The potential for beneficial iron chelation of deferasirox at less than the recommended 20-mg/kg dose was demonstrated. On the contrary, poor tolerability was documented, with adverse events such as severe infections, especially in MDS patients. Although it was not clearly demonstrated that deferasirox was responsible for impaired immunity, careful watching is required to administrate deferasirox.


Introduction
Patients with hematological disorders such as myelodysplastic syndrome (MDS) and aplastic anemia (AA) frequently require ongoing red blood cell (RBC) transfusion support.The frequent transfusions result in iron overload, leading to increased non-transferrin-bound iron, which generates toxic oxygen free-radicals and damage to multiple organs such as skin, liver, heart, pancreas, and other organs [1][2][3].As previous observations have demonstrated that severe iron overload is associated with increased morbidity and mortality, iron chelation therapy is important [4][5][6].Deferoxamine (DFO) is a chelation medication that has been effective at achieving a negative iron balance when applied to patients with transfusion-related iron overload [7,8].On the other hand, DFO requires intravenous injection or subcutaneous administration every day, resulting in impaired quality of life.By contrast, deferasirox is a once-daily, oral iron chelator approved for the treatment of chronic iron overload due to blood transfusions [9][10][11][12][13].The EPIC (Evaluation of Patients' Iron Chelation with Exjade™) study indicated that the overall median serum ferritin level decreased significantly with deferasirox administration, both in chelation-naïve patients and those previously receiving chelation treatment [10].The current treatment guidelines, based on these clinical studies and expert consensus, recommends chelation therapy for transfusion-dependent patients with serum ferritin levels > 1000 ng/mL, depending on the transfusion rate [14][15][16].In Japan, deferasirox was approved 2-year Experience at a Single Institution in Japan about two years ago, and data such as efficacy and tolerability have accumulated; however, there have been few publications regarding its use in clinical practice.In this retrospective study, we share our 2-year experience of deferasirox regarding clinical outcomes including adverse events (AEs).

Methods
Deferasirox was given to 18 hematological disorder patients with serum ferritin levels of >1000 ng/mL due to frequent RBC transfusion.The starting dose was individualized according to blood transfusion frequency or age.Routine clinical laboratory data regarding CBC, liver, renal, and other functions were followed, and serum ferritin was assessed every 4 weeks.Efficacy was evaluated as a change in the serum ferritin level and clinical indicators (frequency of transfusion, skin pigmentation, liver function, cardiac function, glycoalbumin, etc., according to the organ damage in each patient).Safety was evaluated by monitoring of laboratory data and a medical physical exam.Dose adjustment was performed according to the physician's discretion based on each patient's clinical indicators.In the present study, there were no patients in whom the serum ferritin values fell to less than 500 ng/mL during the clinical course.
All patients had received previous DFO administration for iron chelation, but had not experienced success with it.In Japan, subcutaneous DFO injection is not permitted, and it is difficult to use intravenous infection every day for chelation.Instead, the patients in this study were given DFO in every transfusion, but the cumulative effect of the transfusions had outweighed its effect, resulting in gradually increased serum ferritin.AEs were graded according to the National Cancer Institute Common Toxicity Criteria (version 3).The interaction between total RBC transfusion units and serum ferritin level in all patients was calculated by the Pearson product-moment correlation coefficient using JMP software (Tokyo, Japan).The data of basal serum ferritin was collected just before deferasirox induction.Changes in serum ferritin levels and overall clinical improvement were analyzed in the 10 patients who could sustain deferasirox administration for at least 6 months.

Deferasirox Administration
The initial and maintenance doses, as well as any dose modifications, were determined according to the physician's discretion, considering renal function, frequency of transfusion, and serum ferritin level.The details of deferasirox administration in each patient are shown in Table 2.The average initiated deferasirox dose was 11.8 mg/kg (range: 6.4 -26.3).The median duration of deferasirox usage was 10.8 months (range: 0.2 -24.5).There were 10 patients who sustained treatment for over 6 months; in this group, the average maintenance dose was 10.8 mg/kg/day (range; 6.4 -17.9).Thirteen of 18 patients finally ceased deferasirox administration, and 5 patients were still receiving deferasirox at the latest observed time point.The changes of serum ferritin in the 10 patients who could continue at least 6 months are displayed in Figure 2. Serum ferritin reduction more than 1000 ng/ml was achieved in 4 patients, and 2 patients had decreases over 3000 ng/ml.Only 1 patient showed a marked increase in serum ferritin levels after deferasirox administration; the serum ferritin level in the other 3 patients was stable.The reasons for discontinuation were infection (n = 6), skin rash (n = 3), nausea (n = 2), thrombocytopenia (n = 1), and fatigue with dry mouth (n = 1), respectively (Table 2).Sixteen of 18  patients (89%) had AEs; all events other than infections were less than grade 3.All infections that appeared in 6 patients were grade 3 or higher.Four of 6 patients were MDS (3 was RAEB, and 1 was RA).Renal dysfunction developed in 3 patients, two of whom were simultaneously receiving cyclosporin (CyA).Improvement of renal dysfunction was observed in these after withdrawal of CyA.Clinical benefits were documented in 4 patients.Patient 1 showed both reduction of transfusion frequency and improvement of skin pigmentation, and 2 patients (patient 11 and 12) showed improvement of skin pigmentation.Patient 9 showed improvement of skin pigmentation, chronic heart failure, diabetes mellitus, and liver dysfunction, as described later.All 4 took deferasirox for at least 6 months.Although dose escalation was attempted in 5 patients, 4 of these attempts failed because of AEs such as diarrhea, appetite loss, and renal dysfunction (data not shown).

Case Presentation
Figure 3 shows a remarkably treatment-responsive 69-year-old male patient with AA, having skin pigmenserum glycoalbumin, cardiac function, and skin pig- mentation in addition to decreasing the serum ferritin level to 2231 ng/ml.Dose escalation was attempted two times, but 1250 or 1500 mg/day administration failed, tation, diabetes mellitus, liver dysfunction and chronic heart failure due to iron overload.His serum ferritin level at the induction of deferasirox was 9423 ng/ml, and the administration of deferasirox had numerous beneficial effects such as the improvement of liver function, and the maintenance dose was defined as 1000 mg (17.9 mg/kg).Though the frequency of transfusion was not changed, the hemoglobin was gradually elevated from its baseline value, showing the effectiveness of deferasirox.CyA was not effective and renal impairment was found, so that CyA had to be eventually stopped.Liver dysfunction, renal impairment, and diabetes mellitus were improved as indicated in Figure 3.Although he had a chronic heart failure leading to a wide cardiothoracic ratio (CTR), deferasirox administration seemed to ameliorate the CTR, from 57% to 43%.

Discussion
Deferasirox, a once-daily oral iron chelator, has been demonstrated in various studies worldwide involving large numbers of patients with a variety of transfusion-dependent anemias, with similar efficacy to DFO at comparable doses.A phase I and extended study in Japan was developed with similar potential efficacy and safety as those seen in several western clinical trials [17].However, there have been few publications regarding the outcome of its usage in clinical practice in Japan.To discuss this point, we collected and analyzed data from 18 patients who have been treated with deferasirox at our institution.
In this retrospective study, there were several important findings regarding the usage of deferasirox in clinical practice.First, this study showed that lower doses (<20 mg/kg) had some extent of clinical efficacy.Previous clinical trials have clearly demonstrated the dose-dependent iron-chelation effects of deferasirox administration, and have implied that at least 20 mg/kg is required for efficacy [18].It was hard to evaluate this effect because there were no patients in the present study who could tolerate a dose greater than 20mg/kg; however, 4 patients who received a dose lower than 20mg/kg showed decreased serum ferritin levels.In particular, the ferritin reductions in 2 patients (patient 7 and 9, receiving 9.9 mg/kg and 17.9 mg/kg, respectively) were more than 3000 ng/ml as shown in Figure 2. Considering that these patients receive 6 units of RBC transfusion per month, deferasirox achieved sustained iron chelation even at lower-than-recommended doses.The clinical course of the latter patient was remarkable (Figure 3), showing improvement of multiple organs with iron chelation, and 7000 ng/dl serum ferritin reduction.
Second, the maintenance dose of deferasirox in 10 patients who sustained at least 6 months of treatment was 10.8 mg/kg on average, less than those of the previously reported clinical studies.The 1-year EPIC study enrolled 1744 patients with transfusion-dependent anemias, of whom 79.6% completed 1 year of treatment; over 90% of these took doses more than 20 mg/kg [19].In this study, we tried with 4 patients to escalate the deferasirox dose over 20 mg/kg, but these escalations failed due to AEs; for some reason, it was difficult to maintain the recommenced deferasirox dose in this study.The phase I clinical study of deferasirox on Japanese patients with transfusion-dependent anemias indicated that the pharmacokinetics-dose relationship was similar in Japanese and Caucasians [17]; hence, this phenomenon was not likely due to race.
Third, the discontinuation rate (72%: 13 of 18 patients) was higher than those of previous studies.For instance, the phase I and extended study in Japan had a discontinuation rate of only 19% (4 of 21 patients) [17].To understand this discrepancy, it is important to focus on the underlying disease.The EPIC study demonstrated that the incidence of AEs and discontinuation in MDS patient groups was higher than those in other anemia patient groups [19], and this study included 10 MDS patients (55 %), of whom 8 ultimately discontinued the medication because of AEs.In addition, with regard to subtypes of MDS, 2 of 5 MDS-RA patients could sustain deferasirox administration at the time of writing, and improvement of skin pigmentation and the reduction of serum ferritin was observed in patient 12; however, all 4 MDS-RAEB patients interrupted the medication because of AEs.Moreover, 3 of them developed severe infections, resulting in fatality in 2 patients.Our data confirmed current consensus-driven guidelines in deferasirox usage, recommending deferasirox usage for low-risk MDS patients, not for high-risk groups such as RAEB or leukemic patients [20].Meanwhile, it was surprising that the leading AE type in this study was infection, and that all of them were severe, i.e., grade 3 or more.It has been suggested that iron chelation therapies enhance immunity against infections, based on the fact that iron overload promotes free radical tissue damage and organ failure, undermines immune protection and facilitates pathogen invasion [21].On the contrary, DFO, an iron chelator, is also a siderophore, which binds iron and transports it into microorganisms to help maintain their activity and grow, and thus exacerbates infections in various immunosuppressive settings [22].Indeed, 46 of 59 dialysis patients who received DFO developed mu-2-year Experience at a Single Institution in Japan cormycosis [23].Of 1774 patients receiving deferasirox in the EPIC study, serious pyrexia (n = 51; 2.9%), pneumonia (n = 23; 1.3%), and sepsis (n = 20; 1.1%) were observed [17].Furthermore, 26 deaths occurred in 341 MDS patients including 3 cases of septic shock [18].Although deferasirox is not a siderophore so it is not clear-cut whether deferasirox might impair immunity against bacteria and fungus as DFO does, the results of the present study cannot rule out the possibility that deferasirox impairs immunity, given the fact that 2 non-MDS anemias developed (patient 1-AA and patient 9-MPN).Further clinical investigation and analysis of this issue will be required.
In summary, the potential for beneficial iron chelation of deferasirox was demonstrated in patients receiving less than recommended 20-mg/kg dose in clinical practice.On the other hand, deferasirox did not show clinical efficacy in high-risk MDS such as RAEB, as in other recent clinical studies.Poor tolerability was indicated by AEs, especially infections, 2 of which became fatal.Considering the fact that 2 non-MDS patients developed severe infection in this study, the possibility of deferasirox-mediated impaired immunity cannot be ruled out.As this was a small study, further investigations in clinical practice are very important to analyze strategies focusing on the real efficacy of deferasirox among transfusion-dependent anemia patients, including ways of addressing the infection issue.

Figure 1 .
Figure 1.Relationship between total transfusion and serum ferritin level at start of deferasirox.A significant correlation between total transfusion units and serum ferritin level was demonstrated (r = 0.85).

Figure 2 .
Figure 2. Change of serum ferritin level under deferasirox administration.Changes of serum ferritin in 10 patients who could sustain at least 6 months of treatment are displayed.The solid line shows the 5 -10 mg/kg administration group (n = 7); dotted line, 11 -15 mg/kg (n = 2), and bold dotted line, 16 -20 mg/kg (n = 1).Serum ferritin reduction more than 1000 ng/ml was found in 4 patients, and 2 patients had over 3000 ng/ml decrease (patient 7 and 9).Only one patient showed serum ferritin elevation under deferasirox administration (patient 16).pt, patient.

Figure 3 .
Figure 3. Case presentation.A 69-year-old male patient with severe-type AA, having skin pigmentation, diabetes mellitus, liver dysfunction and chronic heart failure due to iron overload was administered deferasirox.The serum ferritin level at the induction of deferasirox was 9423 ng/ml.The administration of deferasirox had remarkably beneficial effects such as the improvement of liver function, serum glycoalbumin, cardiac function, and skin pigmentation in addition to decreasing the serum ferritin level to 2231 ng/ml.Attempts to escalate the dose of deferasirox failed due to diarrhea, resulting in a 1000-mg maintenance dose.The solid line shows the change of serum ferritin, and the dotted line shows the change hemoglobin (Hb).AST, aspartate aminotransferase; ALT, alanine aminotransferase; CRTNN, creatinine; CTR, cardio-thoracic ratio.

Table 2 . Clinical course.
*1. Duration of deferasirox administration.*2.Indicated the data of patients with recieving deferasirox over 6 months.*3.According to NCNI version 3. *4.At the time of the final confirmed date.T/F, transfusion; skin, Skin pigmentation; Herat, chronic hear failure; DM, diabetes mellitus; Liver, liver dysfunction.2-year Experience at a Single Institution in Japan