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Blood Cells, Molecules, and Diseases j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y b c m d

Oral chelators in transfusion-dependent thalassemia major patients may prevent or reverse iron overload complications Kallistheni Farmaki ⁎, Ioanna Tzoumari, Christina Pappa Thalassemia Unit, General Hospital of Corinth, 1, Dervenakion, Corinth 20100, Greece

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Article history: Submitted 10 March 2011 Revised 19 March 2011 Available online xxxx (Communicated by G. Stamatoyannopoulos, M.D., Dr. Sci., 21 March 2011) Keywords: Thalassemia major Combined chelation Deferiprone Deferasirox Iron overload complications

a b s t r a c t Combined chelation treatment may be a better approach for transfusion-dependent thalassemia major patients with iron overload complications because of increased efficacy. Combination therapy with desferrioxamine and deferiprone has already been reported to improve survival dramatically by reversing cardiac dysfunction and other endocrine complications. Some patients have intolerance or inconvenience to parenteral desferrioxamine. The hypothesis of this study was that combining two oral chelators, deferiprone and deferasirox, might lead to similar results. Following approval by the hospital ethical committee and a written informed consent from each patient, 16 patients who fulfilled the criteria participated in a study protocol for a period of up to 2 years. Efficacy measures analysis demonstrated a statistically significant decrease of total body iron load as estimated by serum ferritin, LIC and MRI T2* indices. Regarding the safety assessment, the incidence of adverse events was minor compared to the associated toxicity of monotherapy of each drug. No new onset of iron overload-related complications was demonstrated. A reversal of cardiac dysfunction was observed in 2/4 patients, while the mean LVEF increased significantly. Regarding endocrine assessment, in 2/8 patients with impaired glucose tolerance, we noted a significant decrease in the mean 2 h glucose in OGTT. Additionally an improvement in gonadal function was observed and one male and one female gave birth to two healthy children without hormonal stimulation. Combined oral chelation in thalassemia offers the promise of easier administration, better compliance and may lead to an improvement of patient quality of life by preventing or even reversing iron overload complications. © 2011 Elsevier Inc. All rights reserved.

Introduction Iron chelation therapy effectively acts to prevent long-term complications of iron overload,- in transfusion-dependent thalassemia major patients. Most complications could be reversible and manageable [1]. Despite the beneficial role of each of the three iron chelators, desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX), some patients keep experiencing significant iron-related complications that influence their quality of life while some complications are life-threatening, probably still leading to increased morbidity. The first plausible explanation is that patients fail to adequately respond to any proposed chelation regimen. Each chelator has different properties influencing the clinical management of iron overload [2]. Additionally, each patient has a different safety and efficacy profile with regards to their response to chelation therapy. Iron excretion is dose dependent with wide subject-to-subject variability. A negative iron balance, which ensures prevention and/ or reversal of iron overload complications, is difficult to achieve with

⁎ Corresponding author at: Thalassemia Unit, General Hospital of Corinth, Dervenakion, Corinth 20100, Greece. E-mail address: [email protected] (K. Farmaki).

monotherapy. On the other hand, increasing the dose of a chelator significantly may lead to an increased possibility of adverse reactions. Adherence to any chelation regimen is most likely one of the primary factors affecting disease-free survival. Combined chelator treatment may be a better approach, especially for patients at an increased risk of developing complications. Combination therapy results in increased iron excretion compared to monotherapy alone. During the last decade, ever since combined chelation with DFO and DFP was introduced [3], overall survival improved dramatically [4]. Even patients with end-stage heart failure survived [5]. Numerous prospective [6] and retrospective studies have suggested the shuttle effect between the two chelators [7] that enhances overall iron excretion [8] and achieves treatment goals with manageable adverse reactions [9]. Likewise, a shuttle effect between DFX and DFO has been demonstrated [10] in heart cell cultures improving chelating efficiency. Effectiveness and safety of the combination regimen with DFX and DFO administered in sequence for more than 2 years was reported in a retrospective study of seven thalassemia major patients [11]. Other studies using DFX and DFO concomitantly have shown promising preliminary results [12]. Another potential combined chelation treatment, of DFP and DFX, has been used as alternative [13] or concomitant therapy [14] in 3 thalassemia major patients for 7–28 months, showing a decrease of

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Please cite this article as: K. Farmaki, et al., Oral chelators in transfusion-dependent thalassemia major patients may prevent or reverse iron overload complications, Blood Cells Mol. Diseases (2011), doi:10.1016/j.bcmd.2011.03.007

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iron overload, especially in the heart and without any significant adverse events. Compliance to any chelation treatment undoubtedly determines prognosis. The available data shows very different results in survival rates for patients complying with chelation treatment as compared to non-compliers [15]. The main reason that leads to non-compliance issues is the fact that chelation does not add up obvious benefits to the patient, as it is not a cure but a treatment of transfusion iron overload. On the other hand, the absence of chelation does not cause any immediate consequences. Besides, since it is a daily treatment, starting at an early age and received throughout the patient life, it results in a significant psychological burden. The conventional treatment with parenteral DFO is extremely cumbersome and leads to poor compliance. The infusions and local reactions may prevent patients from having a normal life. In the last decade, the availability of the two oral chelators, DFP or DFX, in the form of tablets or a liquid formulation and dispersible tablets, has offered significant advantages with respect to improving patient compliance to therapy. Our group has had significant experience with the use of combined chelation regimen of DFO and DFP in the last decade [9,16]. We have managed to control iron overload and its complications in the majority of our patients. Taking our significant experience into account as well as all the reports and publications on combined chelation, which have consistently demonstrated achievement of treatment goals with manageable adverse effects, we set out to evaluate a new combination of the two oral chelators (DFP and DFX) in patients who had already presented with serious adverse reactions to DFO and could not comply to the thus far proposed chelation treatment of DFO and DFP. Our primary endpoint was to evaluate the efficacy by measures of total body iron load (mean ferritin, LIC, MRI T2*L and T2*H). Safety was monitored by a close clinical and laboratory investigation of adverse reactions. Our hypothesis was that the new combined oral chelation might prevent or reverse iron overload complications. Patients and methods Patients All participants were transfusion-dependent thalassemia major patients, who were intolerant to parenteral chelation with DFO, or for whom parenteral chelation with DFO was perceived as inconvenient and therefore refused to continue with it. Patients were eligible for participation in this study if they were older than 20 years, had serum ferritin levels N500 μg/l and presented with more than one iron overload complication as defined by clinical and laboratory criteria. Patients who needed an occasional intensification of chelation treatment were also included in the study. Children and adolescent patients were excluded from participation in this study. Additionally, patients who had a history of adverse reactions to either DFP or DFX were excluded from participation in this study. This was an open-label, observational, single centre study conducted in the Thalassemia Unit, of the General Hospital of Corinth, Greece, for a period of 2 years, from December 2008 to December 2010. The study was approved by the hospital ethical committee and written informed consent was obtained from all patients. In addition we sought and received permission to review the charts and analyze the data on the patients with respect to efficacy and safety of the proposed treatment. Chelation regimen The doses of the two oral chelators administered in combination were 75–100 mg/kg/day for deferiprone (DFP) in three divided doses and 20–25 mg/kg for deferasirox (DFX) once a day. The regimen was individualized on the basis of each patient iron overload and specific complications. For patients with heart and endocrine complications

doses were adapted to 100 mg/kg/day of DFP and 20 mg/kg/day of DFX; the DFP dosing scheme was based on data reporting the effectiveness of the drug at removing iron from heart and the endocrines glands [5,9]. On the other hand, patients with liver iron overload received 75 mg/kg/day of DFP and 25 mg/kg of DFX, as the latter has demonstrated effective reduction of the LIC [17,18]. Primary endpoint measures Regarding efficacy we analyzed changes in mean serum ferritin levels (CMIA Architect Abbott) on a monthly basis, as well as quantification of heart and liver iron load (Signa-MRΙ 1.5 T, multiecho T2*) and liver iron concentration (LIC) in mg/g dry weight (g dw) derived from the T2*L value by Ferriscan [19,20] annually. Safety Safety was evaluated by close clinical and laboratory monitoring of adverse reactions, according to the Novartis updated SPC [21] and the ApoPharma full prescribing information (EMEA) [22]. A full check up of each patient was implemented before protocol initiation. At each visit, a history for gastrointestinal disorders, arthralgia, rash or other symptoms was checked by clinical staff as well as a complete whole blood count with absolute neutrophil count (ANC). A monthly evaluation of liver function (serum aminotransferases: ALT, AST and bilirubin) and renal function (creatinine, glomerular filtration rate: e-GFR, calculated by the “4-variable MDRD” formula using serum creatinine, age, race, and gender [23] and proteinuria by a dipstick test) was performed. Auditory and ocular exams, including slit lamp examinations and dilated fundoscopy, were performed yearly. Dose discontinuation or adjustment was considered according to SPC warnings. In the event of infections or pyrexia, both DFP and DFX were interrupted temporarily (mean duration 7 days). Secondary outcome measures were scheduled for iron load complications. Cardiac function was assessed annually, with tissue Echo-Doppler imaging TD and patients were classified according to the New York Heart Association (NYHA) functional classification [24]. Endocrine function was longitudinally assessed at baseline and after 12–24 months: glucose metabolism, by oral glucose tolerance test (OGTT), performed with 1.75 g glucose/kg body weight (maximum 75 g Dextro-OGT; Roche Diagnostics, Mannheim, Germany), in the morning after a 12 h fasting period. Samples were taken at 0, 30, 60, 90, 120 min for glucose evaluation. The area under the curve (AUC) of glucose was also assessed. Diabetics were given a meal equivalent after fasting and 2 h glucose was measured. Patients were classified according to fasting and 2 h glucose [25]. Normal glucose metabolism was defined as fasting glucose b 110 mg/dl and 2 h glucose level b 140 mg/dl; impaired glucose tolerance (IGT) as 111 mg/dl N fasting glucose ≤ 125 mg/dl and 141 mg/dl N 2 h glucose level ≤ 199 mg/dl; and non-insulin dependent diabetes (type II) as fasting glucose N126 mg/dl and 2 h glucose level N200 mg/dl. Thyroid function was assessed by TSH and FT4 screening. Gonadal function was monitored by morning samples of peripheral hormone levels: testosterone and free testosterone or estradiol and progesterone. In addition, serum basal levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) were assayed. Gonadotrophin response was also tested after intravenous infusion of 200 μg gonadotrophin-releasing hormone (GnRH). Samples were taken at 0, 30, 60, 90, 120 min for the measurement of FSH and LH. All analyses were performed by CMIA technology using the automatic immunoanalyzer Architect, i2000SR, Αbbott. Statistical analysis All statistical analyses were carried out using the statistical package for the social sciences software (SPSS release 13.0, Chicago, IL, USA). We evaluated differences between baseline and follow-up

Please cite this article as: K. Farmaki, et al., Oral chelators in transfusion-dependent thalassemia major patients may prevent or reverse iron overload complications, Blood Cells Mol. Diseases (2011), doi:10.1016/j.bcmd.2011.03.007

K. Farmaki et al. / Blood Cells, Molecules, and Diseases xxx (2011) xxx–xxx

values of the studied variables using the paired t-test for normally distributed variables or the Wilcoxon signed-rank test otherwise. Continuous variables are presented as mean ± standard deviation (SD). All p values were two sided; the level of significance is b0.05 and confidence intervals are referred to 95% boundaries.

Results Patient recruitment

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Effect on glucose metabolism Of the 15 patients completing the study, at baseline 8/15 (53%) had abnormal glucose metabolism, either treated diabetes type II [2/15 (13%)] or impaired glucose tolerance (IGT) [6/15 (40%)] as shown in Table 2. Following 24 months of combined oral chelation, mean 2 h glucose in OGTT decreased significantly (111 ± 24 vs. 150 ± 87 mg/dl, p = 0.007) (Fig. 5) and also post-challenge glycaemia as calculated by the area under the curve (AUC) (15,195 ± 2501 vs. 17,100 ± 8817, p = 0.0007).

Sixteen transfusion-dependent thalassemia major patients (9 males and 7 females), aged from 20 to 45 years old (mean: 35 ± 7.5), who had intolerance or inconvenience to parenteral chelation with DFO and presented with more than one iron-related complication or needed an occasional intensification of chelation treatment, were included in this study. Two of 16 had presented generalized anaphylactic reactions to DFO (1 angioedema and 1 respiratory distress syndrome), 10/16 had severe local reactions to DFO (swelling, induration, pain, vesicles, crust, eschar, wheal formation), 3/16 had indication for intensive chelation (2 in preparation for pregnancy by IVF and 1 prior to starting treatment for hepatitis C). One patient discontinued the study after experiencing serious generalized rash 1 week after DFX administration. Finally 15 patients completed the study protocol and were analyzed at baseline and after 24 months.

Effects on gonadal and thyroid function

Effect on total body iron load

Safety assessment

The efficacy of oral combined chelation (DFP & DFX) was demonstrated by a statistically significant decrease of total body iron load. Compared to baseline, after 24 months of combined chelation, there was a decrease in serum ferritin (p = 0.0001) and LIC (p = 0.0019) and an increase in MRI T2*L (p = 0.0012) and MRI T2*H (p = 0.0381), as shown in Table 1. Although at baseline 60% of patients had liver iron loading, 3/15 with moderate hepatic hemosiderosis (T2*L: 4.1–9.0 ms) and 6/15 with mild hepatic hemosiderosis (T2*L: 9.1–19 ms), after 24 months of combined oral chelation all patients normalized their T2*L values.

No deaths nor any serious unexpected adverse events have been observed. The incidence of adverse reactions was minor and comparable to each drug monotherapy-associated known toxicities: Only 3/15 (20%) patients presented transient gastrointestinal upset which were alleviated after symptomatic treatment and temporary dose adjustments of both drugs. No episodes of cytopenias, including agranulocytosis, neutropenia and thrombocytopenia, were observed. The average of the pretreatment measurements for serum creatinine was 0.9 mg/dl and for e-GFR 95 ml/min/1.73 m2. The overall changes across the study period were mild: mean serum creatinine: 1 mg/dl (mean % change = 0.04 ± 0.14) and mean e-GFR: 89 ml/min/1.73 m2 (mean % change = − 0.03 ± 0.18). As the mean changes may not reflect the individual trend in creatinine uniformly in all patients and normal creatinine ranges differ from male to female, we analyzed data for each patient, separating into two groups, males and females (Figs. 1 and 2). For 7/15 (47%) patients pre- and post-treatment creatinine remained unchanged, for 6/15 (40%) increased slightly (0.1 mg/dl) and only for 2/15 (13%) male patients creatinine increased moderately (0.2 mg/dl) but still was within normal values. A more accurate index for renal function, e-GFR was also analyzed. But as it is only an estimate, we have to keep in mind that it may be influenced by different factors like short stature which happens to be prevalent in thalassemia major patients. More credible is the overall analysis of the e-GFR trends if they are progressively worsening, or not (Fig. 3). In 7/15 (47%) baseline e-GFR remained unchanged or increased, in 6/15 (40%) decreased slightly and only in 2/15 (13%) male patients e-GFR decreased moderately between 74 and 88 ml/ min/1.73 m2 Additionally in 3/6 patients the protein dipstick grading

Effect on cardiac function As estimated by LVEF (normal value for TMP N 63%), at baseline, 4/ 15 (26.6%) patients had cardiac dysfunction (1 on NYHA Class II, with slight to mild limitation of activity; comfortable with rest and 3 on class I, with no limitation of activities; they suffered no symptoms from ordinary activities). After combined oral chelation, mean LVEF increased significantly, with 95% confidence intervals (65 ± 7.6 vs. 61 ± 6%, p = 0.0014) as shown in Fig. 4. No new onset of cardiac dysfunction was observed and improvement was detected in the 2 patients of class I, who increased their LVEF to normal. Additionally the patient with NYHA class II exhibited an improvement of symptoms and also progressed from mild iron overload (T2*H: 16.4 ms) to normal and to NYHA class I. Moreover, the mean T2*H of all patients included in the study, although normal at baseline, further increased significantly (p = 0.0381).

Overall, 8/15 (53%) patients (2 males and 6 females) were hypogonadal on hormone replacement therapy at baseline. Two of the females had primary and four, secondary amenorrhea. All females improved in their LH and FSH responses to GnRH test, although their peripheral hormone levels remained unchanged. Among male patients, either hypogonadal or eugonadal, all improved their LH responses to GnRH test, though FSH levels remained unchanged. All males increased their mean testosterone level (9.5 ± 1.8 vs. 7.6 ± 2.4 ng/ml) No new cases of hypogonadism were observed. Regarding thyroid function 2/15 (13%) patients had subclinical hypothyroidism at baseline. One of them presented with a slight increase in FT4 levels and reduced his thyroxin dose. No new cases of hypothyroidism were observed.

Table 1 Total body iron load estimation as assessed by serum ferritin, LIC, MRI T2* at baseline and after 12–24 months of combined oral chelation. n = 15

Normal values

Baseline

After DFP + DFX

p

Serum ferritin (μg/l) LIC Ferriscan™ (mg/g dw) Signa-MRI T2*liver (ms) Signa-MRI T2*heart (ms)

50–120 b 1.5 N 19.1 N 22

581 ± 346 1.6 ± 1.1 18.6 ± 8.9 34.1 ± 5.8

103 ± 60 1.0 ± 0.2 30.5 ± 5.9 36.9 ± 5.6

p = 0.0001 p = 0.0019 p = 0.0012 p = 0.0381

Mean % change paired t-test paired t-test paired t-test Wilcoxon signed-rank

−0.59 ± 0.41 −0.34 ± 0.30 0.99 ± 1.1 0.13 ± 0.23

Please cite this article as: K. Farmaki, et al., Oral chelators in transfusion-dependent thalassemia major patients may prevent or reverse iron overload complications, Blood Cells Mol. Diseases (2011), doi:10.1016/j.bcmd.2011.03.007

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K. Farmaki et al. / Blood Cells, Molecules, and Diseases xxx (2011) xxx–xxx

Fig. 1. Overall individual trends of creatinine changes in male patients.

Fig. 3. Overall individual trends of e-GFR in thalassemia patients.

varied from trace + (5–20 mg/dl, less than 0.5 g/day) to trace +++ (300 mg/dl, 1–2 g/day). In the first 6 months of the study some transient elevations of transaminases (SGPT/ALT levels N2 times the upper normal limit) occurred in 2/15 (13%). Neither auditory nor ocular changes were observed.

This was further confirmed by LIC, a more accurate index of total body iron stores, which also decreased to normal levels (1.0 ± 0.2 mg/g/ dw). LIC changes reflected a dramatic increase of MRI T2*L from moderate to upper normal limit with a spectacular mean change of 99% and improvement in liver function. The role of chelation therapy is crucial in maintaining low LIC levels and preventing progression of fibrosis to cirrhosis particularly in patients with HCV chronic hepatitis infection [28]. For this reason one of our inclusion criteria was the intensification of chelation therapy prior to treatment for hepatitis C infection. Iron overload of the liver may also play a role in the fertility potential of female patients [29]. Thus, we considered of benefit to include in the study females that were planning pregnancy, even through IVF. Moreover, a liver free from iron prior to pregnancy is of benefit to patients, as iron overload increases during pregnancy because of chelation discontinuation. Finally, DFP and DFX combination was beneficial to patients intolerant or experiencing local reactions to parenteral chelation with DFO, in reducing serum ferritin levels, as well as LIC [30].

Discussion Total body iron assessment

Prevention and/or reversal of iron overload complications With the combined oral chelation, not only cardiac but also endocrine complications could be preventable, even reversible in some cases. Our study in 15 patients further confirmed the improvement in cardiac iron status and cardiac function originally reported in the first study of concomitant use of DFX and DFP in 3 patients [14]; we additionally demonstrated a significant increase in

60 40

50

LVEF

70

80

In our study, the combined oral chelation treatment of DFP and DFX has proven to be effective in reducing iron overload to normal levels. Historically, the target levels for control tissue iron have been limited by the increased frequency of DFO-mediated toxicity and most treating physicians have a reluctance to reduce serum ferritin lower than b500 μg/l. With newer chelation regimens, these limitations may not be the same [26]. Since patients continuously load with iron, as a result of their transfusion regimen, even if ferritin reaches normal levels it is unlikely that this would result in iron deficiency. It is now well established that low serum ferritin levels do not necessarily reflect low iron stores. Moreover ferritin levels provide insufficient information about the iron loading trends in tissues of various organs such as the heart [26] and the endocrine glands. To date, significant reduction of iron burden and normalization of iron stores, achieved by combined treatment of DFP and DFO, has been reported in a few cases [9,27]. This study demonstrated a significant decrease in serum ferritin to normal levels (103 ± 60 μg/l), with a mean change of 59%.

baseline

Fig. 2. Overall individual trends of creatinine changes in female patients.

after treatment

Fig. 4. LVEF (mean change 9%) at baseline and after 2 years of combined oral chelation DFP and DFX.

Please cite this article as: K. Farmaki, et al., Oral chelators in transfusion-dependent thalassemia major patients may prevent or reverse iron overload complications, Blood Cells Mol. Diseases (2011), doi:10.1016/j.bcmd.2011.03.007

K. Farmaki et al. / Blood Cells, Molecules, and Diseases xxx (2011) xxx–xxx Table 2 Glucose metabolism classified according to fasting and 2 h glucose: at baseline and after 24 months of combined oral chelation DFP and DFX. Glucose metabolism (n = 15)

Baseline

After DFP + DFX

Diabetes type II (glucose 0 min N 126 mg/dl 2 h N 200 mg/dl) Impaired glucose tolerance (glucose 0 min N 111 ≤ 125 mg/dl and 2 h N 141 ≤ 199 mg/dl) Normal (glucose 0 min b 110 mg/dl 2 h b 140 mg/dl)

2

1 changed over to IGT 1 ameliorated but under Ttmt Reversal in 2 4 normal but under Ttmt

6

7 (46.6%)

9 (60%)

the mean LVEF. However, this is the first study of combined oral chelation to our knowledge, to point out prevention and/or reversal of endocrine complications. Up to now this has been reported only as a result of intensive combined chelation with DFO and DFP [31]. Endocrine complications become more frequent in long-term survivors and substantially affect their quality of life. Their frequency differs among countries depending on different chelation regimens and on the overall life style [32]. Virtually all endocrine glands can be affected and one or more endocrine dysfunction might be present in the same patient. Usually, in the early stages of the disease, where patients are likely to be asymptomatic, only peripheral glands are impaired. In heavy iron overloaded patients the anterior pituitary might also be damaged and regulatory hormonal secretion (LH, FSH, and TRH) may be disrupted [33]. Our data show that once the toxic iron is gone, the body repair mechanisms could swing into action to correct the damage that might have occurred. Additionally, the combined oral chelation scheme seems to provide sustained reduction in labile plasma iron (LPI) and cellular labile iron (LCI), which through oxidative stress pose a threat to cell integrity and triggers apoptosis leading to organ dysfunction [34]. On the contrary, DFO with its high molecular weight and low lipophilicity does not favor cellular uptake [35]. A report on DFO effect on NTBI [36] mentioned that it removed only about a third of NTBI, and intermittent infusions of high-dose DFO might lead to a greater rebound in NTBI on their cessation. On the other hand, the two oral chelators DFP and DFX are relatively small molecules with requisite partition coefficients that confer upon them high membrane permeability and thereby also high cell iron extraction capacity [37]. DFX at a dose ≥20 mg/kg/d was reported to provide 24-h protection from LPI [38]. DFP with its additional property of redistributing iron within and among cells [39] affects iron status both as a mobilizer of tissue iron and as an effective scavenger of labile plasma iron [40].

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Cardiac function It is well known that heart failure is the leading cause of death in thalassemia major patients (71%, mean age 35 years in the UK) [41]. A number of publications have reported that with parenteral chelation DFO, despite excellent compliance, minimal liver iron and wellcontrolled serum ferritin levels, patients may still develop cardiomyopathy by progressive myocardial iron deposition [42]. In a number of reports to date, DFO does not adequately prevent myocardial siderosis [43,44]. In comparative studies of DFO and DFP, it was reported that oral DFP was more effective than DFO in removal of myocardial iron [45] and mainly at a significantly faster rate [46]. DFP has been shown to be effective in severe cardiac iron overload [47]. In a randomized, placebo-controlled, double-blind trial [6] the combination of DFP and DFO was shown to be more effective than DFO alone in reducing myocardial iron and improving LVEF in patients with mild to moderate cardiac iron loading. Finally, in a prospective multicenter study [48,49] it was reported that DFX 30–40 mg/kg/d removed iron from the heart and maintained LVEF in patients with mild, moderate, and severe myocardial siderosis, and also improved LVEF in patients with normal myocardial iron. Similar findings were also reported in another prospective study [50] and other retrospective observations [51,52]. Moreover the concomitant use of DFX and DFP in 3 patients [14] demonstrated an increase in T2*H MRI for all patients, while one patient also showed an improvement at their LVEF. The data from the present study in 15 patients shows a 2–3 fold increase in the mean percentage of change in MRI T2*H and additionally a 9% in the mean change of LVEF in all patients. Although our patient population had a normal pretreatment T2*H and moderate iron overload in the liver, at baseline 4/15 (26.6%) had cardiac dysfunction (1 NYHA class II and 3 Class I). It has already been reported that although cardiac T2* values below 20 ms may be correlated with cardiac dysfunction, different values above this cut-off do not exclude clinical symptoms [53]. It has also been reported that there is a complex relationship between cardiac iron and total body iron burden. Iron deposits were found not to be proportionally distributed between the liver and the heart or uniformly distributed within each organ [54]. Iron mobilization in each patient varies and iron deposits in each organ are cleared at different rates [49]. The significant increase in the mean LVEF (p = 0.0014) strongly supports the hypothesis that an improvement in LVEF may occur after complete myocardial iron clearance and even when total body iron is cleared [49]. As no new onset of cardiac dysfunction was observed, our results suggest that this combined oral chelation may be useful in preventing or reversing cases of cardiac disease. Glucose metabolism

Fig. 5. Two hour glucose, after oral glucose challenge (mean change 19%), at baseline and after 2 years combined oral chelation DFP and DFX.

While on DFO monotherapy, 78% of our patients had glucose metabolism abnormalities (based on criteria of WHO and the American Diabetes Association). Other authors [55,56] reported that with DFO, patients typically experience a gradual decline in glycaemic control even with optimal treatment compliance [32]. In our previous reports, after 5–7 years of combined chelation with DFO and DFP this proportion declined to 34% and overall, patients experienced a significant shift (Fisher's exact test, p b 0.001), either to less severe forms of glucose abnormality or to complete remission [57]. These findings were confirmed by another group [58] but their differences failed to reach statistical significance, probably due to the less intensive chelation regimen (mean ferritin levels remained above N1500 mg/l). The improvement of our patients persisted over time, despite the fact that patients experienced a significant increase in body mass index (BMI), consistent with the hypothesis that effective iron chelation per se was sufficient to improve glucose metabolism. Our study suggests that with oral combined chelation with DFP and DFX, a prevention or reversal of glucose metabolism abnormalities

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may also be possible. One of the two patients with treated type II diabetes changed over to IGT and the other improved his 2 h glucose level. Among patients with IGT (6/15), 2 normalized their glucose metabolism and the remaining 4, who were on oral antidiabetic treatment, normalized their 2 h glucose in OGTT, but still remained under treatment with a dose reduction. There was a statistical difference in all patient mean 2 h glucose as well as in post-challenge glycaemia with a mean change of −19% and −20%, respectively. These results support the idea that early intervention with intensive chelation may reverse the affected pancreatic function. It has been reported that the main risk factors associated with diabetes in this group of patients were advanced age and LIC N 4 times above the normal value or liver fibrosis or severe cirrhosis [59]. Eventually the improvement from moderate liver iron overload to an iron free liver in our patients contributed to the improvement of glucose metabolism abnormalities. As a relationship has been defined [60] between pancreatic and heart iron deposition, which seems to be preceding the cardiac iron loading, perhaps the significant increase in mean MRI T2*H over the normal limits and the further increase in LVEF supported the above improvement. Gonadal function It is worth mentioning that an improvement in gonadal function has been seen in men and women alike. Hypogonadism is the most frequent complication in thalassemia major patients and affects patient quality of life dramatically as it relates to fertility issues and the impact it may have on their psychological wellbeing. It may result from iron deposition either in the hypothalamic-pituitary cells, resulting in an insufficient secretion of gonadotrophins (FSH/LH) and/or in the gonads, due to direct damage of testis/ovaries. In a previous DFO and DFP combination study [9], while on DFO monotherapy, 70% of our adult patients were hypogonadal, after 5–7 years of combined chelation with DFO and DFP, 50% of the males achieved normal testosterone levels, normalized their LH and FSH during GnRH stimulation test and discontinued testosterone replacement therapy. Of note is that 2 of these patients have parented children (one of twins). Among female patients, 6 have become pregnant, 2/6 despite primary amenorrhea after in vitro fertilization (IVF) and 4/6 with secondary amenorrhea spontaneously. All delivered healthy infants. During our current study of 2 years with combined oral chelation with DFP and DFX, we noted an improvement of LH and FSH responses to GnRH test in females. In males an increase in LH and in mean testosterone level was observed. One male and one female gave birth to 2 healthy children without hormonal stimulation. These improvements as well as the fact that no new onset of hypogonadism has occurred during the study overall indicate that the protocol may be beneficial with respect to gonadal function. Safety evaluation was performed by close clinical and laboratory monitoring. Any medication has possible adverse events, which may be unpredictable patient-specific, depending on complex interactions between genetic polymorphisms and the environment [61]. In our current study, we observed neither an increase in the incidence nor any unexpected adverse events compared with monotherapy of each drug alone. Close evaluation of each patient is mandatory before starting treatment in order to detect possible risk factors [18]. Patient information about potential adverse events or medication interactions and clear instructions to seek medical attention immediately as well as early intervention and management on the part of the therapeutic team eventually promoted minimization of adverse effects, which were ultimately resolved. Regarding gastrointestinal disturbances, which are the most common drug-related adverse events for both medications, we proceeded by testing symptomatic patients for Helicobacter pylori and, if positive, by treating the infection with the eradication treatment regimen. We also noted that it might be beneficial for patients to take DFX in the evening rather than the morning. Concerning serum transaminase (AST/ALT) increases, which both drugs may be respon-

sible for, they were moderate, asymptomatic, transient and were not regarded as a reason for treatment discontinuation or dose reduction. Effect on renal function In a study on DFX [62] increases in serum creatinine were mild, nonprogressive, and occurred in about 36% of patients. In our study, serum creatinine analysis according to sex demonstrated that all patient measurements were within normal range. Two of 15 (13%) presented an increase in serum creatinine, equal to 30% above the average of the pretreatment measurements, which after a brief discontinuation of DFX returned to pretreatment values. These two patients had a pre-existing cardiac dysfunction, which had already reversed and one of them was under ACEI treatment (expected to increase creatinine levels up to 30%). DFX was reinitiated at 10 mg/kg/day followed by gradual escalation to a final dose of 15 mg/kg/day. In order to make sure that kidney function was not affected, we also analyzed e-GFR individual trends (Fig. 3). According to the American Kidney Foundation criteria [23], at baseline only 9/15 (60%) vs. 6 (40%) post-treatment had normal kidney function (e-GFRN 90 ml/min/1.73 m2 and no proteinuria). Among 6/15 with an abnormal e-GFR at baseline, probably due to other individual risk factors (short stature, diabetes or cardiac dysfunction), in 5/6 e-GFR remained unchanged and fluctuated between 83 and 89 ml/min/1.73 m2 and only in the remaining 1/6 e-GFR declined to 68 ml/min/1.73 m2. This patient presented with additional co-morbidities (diabetes type II and a pre-existing cardiac dysfunction which had already reversed). A decline of e-GFR was also noted (min levels 74; max 89) in 4/15 patients with normal e-GFR at baseline. As there are fluctuations from one measurement to the other, the average of each individual patient may be used. Finally, 5/15 (33%) patients presented with decline of e-GFR compared to the baseline values but changes were not considered clinically significant. Trace of proteinuria was present in 3/15 (20%) of patients. In 2/3 the trace of proteinuria was + (5–20 mg/dl, less than 0.5 g/day); both of them had type II diabetes. In the remaining 1/3 the proteinuria trace was +++ (300 mg/dl, 1–2 g/day) while this patient had pre-existing renal lithiasis. Based on our experience, we would suggest that patients with predisposing factors (diabetes type II, renal lithiasis or ACEI treatment) should not be administered more than 15–20 mg/kg/day of DFX in order to preserve their renal function [20]. In any case, with the use of combined oral regimen the overall safety profile of DFX and DFP in adult patients was similar to that when the drugs were used as monotherapy. Compliance Managing patient expectations can be the first step toward achieving long-term treatment goals. It can be challenging to keep transfusion-dependent patients complying with a chronic chelation therapy for an asymptomatic condition like iron overload. If patients are not feeling the beneficial effects of their therapy and particularly if they experience adverse events, they are not motivated to comply with the proposed treatment. One longitudinal multicenter, ItalianTHAlassemia-Cost-&-Outcomes-Assessment (ITHACA) [63] has previously reported a decrease in patient satisfaction and acceptance of their chelation treatment by DFO, as the overall benefits were not always perceived as optimal. Another prospective, open-label, 1-year, multicenter study in the Middle East (ESCALATOR) [64] demonstrated that patients had greater satisfaction and convenience with DFX compared to DFO, something that improved compliance and overall patient wellbeing. One of the simplest ways to help patients overcome the compliance challenges is the chelation calendar. This may be kept by the patient every day and reviewed by the treating physician at relevant time periods. The physician should make notes of the monthly serum ferritin results and of the remaining total body iron load indices annually. Likewise, not only can the doctor understand if the patient is responding to treatment and whether a dose adjustment

Please cite this article as: K. Farmaki, et al., Oral chelators in transfusion-dependent thalassemia major patients may prevent or reverse iron overload complications, Blood Cells Mol. Diseases (2011), doi:10.1016/j.bcmd.2011.03.007

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may be needed but also the patients are monitoring their iron levels and getting the reassurance they need that their therapy is working and the motivation to comply to it long term. Another motivation is to include the patient in the decision-making. Patients, who had presented intolerance or inconvenience to parenteral chelation with DFO, imperatively expressed the need to get rid of the burden of parenteral infusions. Being able to get rid of the infusion pumps, which limit their daily activity and influence their relationships, has revolutionized their everyday life and improved their quality of life. Study design (strengths and limitations) To our knowledge, this is the first study analysis to point out that the therapeutic goals of prevention and/or reversal of endocrine complications may be achieved with the use of combined oral chelation regimen of DFP and DFX, after 24 months of treatment. It also underlines the advantages of DFX vs. DFO in combined chelation. Additionally it suggests that a DFX dose of 15–25 mg/kg/day used in a combined oral chelation regimen is safe enough even with low levels of iron overload. This study analysis presents several limitations in that it is a longitudinal, observational study, with a limited size sample of adult patients with moderate iron overload. Further randomized controlled trials are required to analyze this issue and to ascertain the efficacy and safety of combined oral chelation (DFP and DFX) to prevent and/or reverse iron overload complications. Conclusion Our study demonstrated that the combined oral chelation regimen was efficient and well tolerated in moderate iron loaded adult transfusion-dependent patients. The availability of orally active chelators, apart from the fact that it offers the promise of easier administration and better compliance, opens up the possibility of combination therapy to target low levels of iron loading which have been limited by the increased frequency of desferrioxamine-mediated toxicity in such cases. Overall, iron excretion is enhanced by selective chelation in specific organs by each drug; the levels of labile plasma iron and labile cell iron may also be maintained persistently low, thereby negating their toxic potential. Combined oral chelation is also beneficial in “non-responding” patients who fail to show a decreasing trend in iron load indices, due either to inadequate dosing in monotherapy regimens or to the occurrence of adverse reactions which are mostly dose dependent or even due to poor treatment adherence. Adverse events are manageable if properly monitored. With the combined oral chelation, not only cardiac but also endocrine complications, which become more frequent in long-term survivors, could be preventable and even reversible in some cases providing a substantial improvement of their quality of life. The effect of DFP in this regard has already been demonstrated; such a response may be seen with DFP-DFX combination protocols as well. It is important now, more than ever, that relevant studies are planned and conducted to further demonstrate such outcomes.

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Acknowledgment To Fotis Panitsas who realized the statistical analysis.

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