Iron-chelation therapy with oral chelators in patients with thalassemia ...

Iron-chelation therapy with oral chelators in patients with thalassemia major Vedat Uygun 1, Erdal Kurtoglu 2 Antalya Egitim ve Arastirma Hastanesi Çocuk Hematoloji Bolumu, Antalya, Turkey, 2Antalya Egitim ve Arastirma Hastanesi Hematoloji Bolumu, Antalya, Turkey 1

In thalassemia major (TM), without iron chelation therapy, iron-mediated free radical damage causes liver, endocrine, and myocardial toxicities. Deferoxamine has universally been the standard therapeutic option for iron chelation therapy; however, its usage is troublesome, leading to suboptimal patient compliance. In order to maximize the effectiveness of iron chelation therapy, oral iron chelators deferiprone and deferasirox constitute an important development, offering a potential to improve compliance. Although both oral drugs are effective, they have differences including different pharmacokinetics and side-effect profiles. Our retrospective evaluation of TM patients using oral chelators showed that oral chelators are effective in reducing iron overload regarding ferritin level and partially in cardiac T2* value. However, in our study side effects and discontinuation rates were unexpectedly high and close follow-up of TM patients using oral chelators should be carefully done. The variability in rate of side effects and drug discontinuation in spelenectomized patients using oral chelators suggests that spleen may have a role in pharmacokinetics of these drugs, as well. Key Words: Thalassaemia major, Oral chelator, Side effects, Splenectomy

Introduction Thalassemia major (TM) patients require regular red blood cell transfusions usually starting within their first year of life, to achieve sufficiently high hemoglobin levels for adequate growth and development. In these patients, iron overload often develops, necessitating iron chelation therapy. Without iron chelation therapy, iron-mediated free radical damage causes liver, endocrine, and myocardial toxicities.1,2 These patients represent a huge global public health problem. β-Thalassemia is a major public health concern in Turkey; the overall frequency of β-thalassemia trait has been reported to be 2% countrywide; however, in certain regions like Antalya, it increases up to 10%.3 Deferoxamine has universally been the standard therapeutic option for iron chelation therapy; however, its usage is troublesome, leading to suboptimal patient compliance because of discomfort associated with the regimen.4 In order to maximize the effectiveness of iron chelation therapy, oral iron chelators deferiprone and deferasirox constitute an important development, offering a potential to improve compliance. Although both oral drugs are effective, they have differences including different pharmacokinetics and side-effect profiles.5 Correspondence to: Vedat Uygun, Antalya Egitim ve Arastirma Hastanesi Çocuk Hematoloji Bolumu, 07100 Antalya, Turkey. Email: [email protected]

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© W.S. Maney & Son Ltd 2013 DOI 10.1179/1607845412Y.0000000046

In regularly transfused TM patients, the need for transfusion varies as a result of differences in spleen activity. Owing to increased consumption of red cells or hypersplenism, the transfusion requirements increase, leading to splenectomy to reduce transfusions. The spleen is the second largest iron depot of the body after liver; moreover, spleen stores largest iron aggregates in the body.6,7 Therefore, splenectomy might result in a diverse effect on iron balance and influence the pharmacokinetic profiles of chelators.8 While simple use of oral chelators makes them an appropriate choice in iron overload, the increasingly serious side effects become a serious issue.9,10 The side effects of oral chelators and the impact of splenectomy on these side effects in patients with TM were investigated in this retrospective study conducted in a state hospital in Turkey.

Methods The current retrospective study analyzed transfusiondependent β-thalassaemia patients, who had a routine of regular 2–4 weekly hospital visits for transfusions and regular cardiac and endocrinological evaluation on every 6 or 12 months depending on the patient’s status. Auditory and visual functions were regularly performed at least annually. Patients who did not have a regular visit for at least 3 months during the follow-up were excluded from the study.

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Splenectomy was performed for deteriorating hypersplenism or when the annual packed red blood cells transfusion requirements rose above 200 ml/kg/ year. The patients enrolled in the study received at least one dose of deferiprone, deferasirox, and combination therapy involving deferiprone and deferoxamine in doses of 40–75, 10–40, and 50–75 mg/kg/ day + 40–50 mg/kg/3–5 days a week, respectively. Clinical data from these patients were obtained retrospectively from medical records on demographic data, dosage of chelators, hepatic enzymes, presence of viral hepatitis, level of ferritin, serum and urine creatinine, urine protein, as well as time and cause of discontinuation of the drug. The side effects related to chelators were observed and they were discontinued only if the liver transaminase levels elevated more than fivefold the upper limit of normal and if there is an abnormality in protein:creatinine ratio (>1.0 mg/mg) at two consecutive assessments, gastrointestinal symptoms decreasing oral intake, and a neutrophil count below 1000/mm3. The patients who interrupted the drug for 1–2 weeks and resumed thereafter in circumstances where neutrophil count dropped below 1500/mm3 in those taking deferiprone and the increment in protein:creatinine was less than 1.0 mg/ml in those taking deferasirox were also enrolled in the study. Although side effects in these patients were recorded, intermittent discontinuation of the drug was not counted as drug discontinuation. Change in myocardial T2* from baseline to at least 6th month was also recorded, when available. When the drug was interrupted, the other oral chelator was tested. Again, when the drug did not respond or side effects developed, only deferoxamine was continued. When gastrointestinal complaints were observed,

Oral chelators in thalassemia major

supportive cares (antiemetic, dose reduction) were applied, but they were discontinued when they did not respond. This study was approved by the State Hospital´s ethics committee. All statistical analyses were performed with SPSS for Windows (Version 16.0). Frequencies and percentages for descriptive statistics of qualitative variables and mean ± standard deviation for descriptive statistics of quantitative variables were calculated. The mean values of each drug groups were compared using the Student’s t-test or Mann–Whitney U test. A P value of less than 0.05 was considered to be statistically significant.

Results A total of 169 transfusion-dependent β-thalassemia patients treated with oral chelators at least one dose between January 2003 and May 2012 were enrolled in the study. Five patients were excluded from the study due to irregular follow ups. The mean age was 21.2 years (range 3.9–58.0 years) at the last day of oral chelator usage. The demographic and clinical data of the patients are shown in Table 1. Thirty-eight patients (23.1%) stopped therapy after the occurrence of side effects, while 10 patients because of deteriorating iron overload, in a total of 29.2% of patients (Table 2). Reassessment of groups in terms of discontinuation of the drug in first year showed that patients taking deferasirox had a discontinuation rate of 13.8% (11/80) before completion of first year whereas patients taking deferiprone had a discontinuation rate of 35% (7/20). Deferasirox was used more often than deferiprone (deferiprone alone and combination therapy) and for a longer duration (36 vs. 28 months; P = 0.007, respectively).

Table 1 Characteristics of patients Deferasirox Number of patients Age (years)* Male/female (n) Initial dose (mg/kg/day) Last dose (mg/kg/day) Duration of treatment (mean months) First ferritin (ng/ml) (median)† Last ferritin (ng/ml) (median)† Highest ALT‡ (U/l) Highest AST§ (U/l) T2* (ms) Number of patients¶ Duration (mean months) First T2* Last T2* P

105 (64%) 21.1 (3.9–58.0) 46/59 19 (10–30) 32 (15–40) 36 (1–112)

Deferiprone alone

Combination

Both

2339 (234–8489) 1679 (215–6645) 77 (14–428) 60 (11–285)

29 (17.7%) 22.9 (5.7–52.8) 15/14 52 (26–75) 70 (35–85) 23 (3 days–88 months) 1781 (405–5983) 1416 (58–5880) 64 (20–510) 49 (23–674)

30 (18.3%) 20.1 (8.4–36.7) 16/14 53 (22–75) 74 (50–90) 33 (2 days–112 months) 3109 (860–8419) 1992 (133–6683) 85 (15–624) 70 (20–349)

59 (36%) 21.5 (5.7–52.8) 31/28 53 (22–75) 72 (35–90) 28 (2 days–112 months) 2049 (405–8419) 1832 (58–6683) 73 (15–624) 49 (20–674)

14 15.7 (6.2–25.3) 14.3 (8.7–19.4) 17.3 (8.7–26.8) 0.16

2 11.9 (10.6–13.3) 14.9 (13.5–16.3) 21.7 (15.5–27.8) –

11 13.8 (8.5–21.8) 13.5 (10.6–16.6) 15.8 (9.6–22.7) 0.19

13 13.5 (8.5–21.8) 13.7 (10.6–16.6) 16.7 (9.6–27.8) 0.10

*Mean age at the last day of chelator. In the patients who used the drug at least 3 months. ‡ Alanine aminotransferase (mean). § Aspartate aminotransferase (mean). ¶ Patients whose first T2* was under 20 ms; last T2* was the last T2* performed at least 6 months after the first T2*. †

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Table 2


Characteristics of side effects and discontinuation Deferasirox

Number of patients Discontinued (n) (%) Discontinuation rate at first year (n) (%) Duration of treatment till discontinuation (mean months) Last ferritin level when disc* (ng/ml) (median) Last ferritin level when not disc* (ng/ml) (median) Last dose† (mg/kg/day) when disc* Cause of discontinuation GIS Neutropenia Increased liver enzymes Proteinuria Increased ferritin Decreased T2* Visual disturbances Total (n) (%) Side effects GIS Proteinuria Neutropenia Increased liver enzymes Auditory disturbances Visual disturbances Rheumatologic Skin rash Total (n1) (n2) (%)‡

105 (64%) 31 (29.5%) 11/80 (13.8%) 23 (1–80)

Deferiprone alone

Combination

Both

2615 (246–6645)

29 (17.7%) 10 (34.4%) 7/20 (35%) 10.3 (3 days–30 months) 2163 (702–5880)

30 (18.3%) 7 (23.3%) 4/25 (16%) 28 (2 days–75 months) 2706 (1282–3351)

59 (36%) 17 (28.8%) 11/45 (24%) 17.5 (2 days–75 months) 2678 (702–5880)

1593 (215–4633)

707 (58–3898)

1780 (133–6683)

1525 (58–6683)

31 (15–40)

69 (35–75)

75 (60–90)

71 (35–90)

7 0 2 10 8 1 3 31 (29.5%)

5 3 1 0 1 0 0 10 (34.4%)

3 3 1 0 0 0 0 7 (23.3%)

8 6 2 0 1 0 0 17 (28.8%)

16 17 0 9 12 4 0 4 (48) (62) (45%)

6 0 3 2 3 2 2 0 (17) (18) (58%)

5 0 4 5 3 0 2 0 (16) (19) (53%)

11 0 7 7 6 2 4 0 (33) (37) (56%)

*Discontinued. Mean. ‡ Percentage of patients who had side effects in the related drug group. n1 total number of the patients who had side effects in the related drug group. n2 total number of side effects in n1. †

Six patients who received the drug for less than 3 months were excluded during the ferritin assessments and it was determined that, as all the drugs were effective in reducing ferritin levels, there was no difference between deferasirox and combination therapy in reducing ferritin levels (mean ferritin reduction 789 vs. 941 mg/ml; P = 0.47, respectively); however, deferasirox reduced ferritin levels more than deferiprone alone (789 vs. 443 ng/ml; P = 0.042, respectively). At the time of discontinuation, there was no significant difference between ferritin levels in terms of the drug used; furthermore, in contrast to low-level ferritin, high level of ferritin was significantly associated with discontinuation (1789 vs. 2604 ng/ml; P = 0.001). The maximum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) reached during the chelation regimen were less than five-fold the upper limit of normal for almost all but nine patients for deferasirox and seven patients for deferiprone (two deferiprone, five combination therapy patients); however, mean levels did not differ significantly across the groups (Table 1). Seven patients were diagnosed with hepatitis (three hepatitis C and four hepatitis B), although liver enzymes in none elevated as much as to require discontinuation of the drug.

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Change in myocardial T2* from baseline to at least sixth month was determined when available. T2* value of 80% of the patients who had an initial T2* value above 20 ms (31 patients) did not drop below 20 ms. Moreover, it showed an improvement in patients with an initial T2* value below 20 ms; however, this improvement was not significant (Table 1). The side effects and causes of discontinuation of oral chelators are shown in Table 2. The frequency of discontinuation was similar between the groups; however, deferiprone was stopped earlier than deferasirox and combination therapy (10.3, 23, and 28 months, respectively). It has been considered that a higher dose may have been used in patients who discontinued deferiprone since these patients had a higher mean ferritin compared to those who did not discontinued the drug; however, there was no significant difference between both groups in terms of the dosage at the day of discontinuation (69 vs. 71, P = 0.60). The most common reason for deferasirox discontinuation was gastrointestinal causes while progressive ferritin elevation was among common causes. The lowest dose was 30 mg/kg/g and mean duration was 28 months (9–56 months) in patients who used deferasirox and had a progressive ferritin elevation.


The side effect rate was similar among chelators. The most common side effect was gastrointestinal side effects while liver enzyme elevation and hearing impairment were other common causes. Although fluctuations occurred in creatinine levels, none was above the age-matched value. Proteinuria was present in 16% of those taking deferasirox while deferiprone-taking patients had a neutropenia rate of 12%. Six of entire population had visual impairment, half of which discontinued drug. Although 18 patients experienced hearing loss, none discontinued the drug and the impairment was reversible after dose reduction. Half of patients had previous splenectomy. Data regarding these patients are given in Table 3. Although 11 patients underwent splenectomy after they had begun taking the drug, they kept taking the drug for 2 months to 6 years. Patients taking deferasirox and having splenectomy had a larger decrease in ferritin compared to those without splenectomy (264 vs. 1324 ng/ml; P < 0.001) whereas splenectomy lacked this significant effect in patients taking deferiprone and combination therapies. Splenectomy increased discontinuation rate in patients taking deferasirox whereas it decreased in patients taking deferiprone (Table 3). Interestingly, proteinuria was more


common in patients with splenectomy (8 (15%) vs. 2 (4%), respectively) and neutropenia was more common in patients without previous splenectomy (5 (15%) vs. 2 (7%), respectively). Splenectomy had no significant effect on duration of drug use in deferasirox whereas non-splenectomized deferiprone patients discontinued the drug earlier, albeit statistically non-significant (Table 3).

Discussion To prevent the onset of complications associated with iron overload in TM, long-term iron chelation therapy is mandatory. Currently, the rate of use of oral chelator is increasing because of compliance issues for deferoxamine. Having specific advantages and disadvantages, oral chelators have very limited amount of comparative studies. We retrospectively studied clinical and laboratory data of 164 TM patients who were using oral chelators in a state hospital in Turkey. Approximately 30% of patients had to stop the drug due to various reasons. In literature, the discontinuation rate is about 10% for deferasirox and about 30% for deferiprone.11–15 In these studies, side effect and discontinuation rates increased as the drug dose increased. Hence, 71% of patients in our study taking deferasirox had a dose of equal or greater

Table 3 Characteristics of splenectomized patients Deferasirox

Deferiprone Alone

Number of patients Splenectomized (n) (%)* Discontinued (n) (%)† Duration of treatment (mean months)

105 (64%) 52 (49.5%) 18 (34.6%) 24.1 (1–80)

29 (17.7%) 15 (51.7%) 3 (20.0%) 18 (8–30)

Non-splenectomized Discontinued (n) (%)‡ Duration of treatment (mean months) Side effects in spl. patients GIS Proteinuria Neutropenia Increased liver enzymes Auditory disturbances Visual disturbances Rheumatologic Skin rash Total (n1) (n2) (% in spl.)§

53 13 (24.5%) 21.3 (1–49)

14 7 (50%) 7 (3 days–24 months)

9 10 0 1 8 3 0 2 (24) (33) (46%) 4 8 0 0 4 2 18 (34.6%)

Cause of disc. in spl. patients GIS Proteinuria Neutropenia Increased liver enzymes Increased ferritin Visual disturbances Total (n) (% in spl.)

Combination

Both

30 (18.3%) 12 (40.0%) 3 (25.0%) 26.1 (2 days–75 months) 18 4 (22.2%) 29 (8–55)

59 (36%) 27 (45.7%) 6 (22.2%) 22.0 (2 days–75 months)

1 0 1 0 3 1 1 0 (7) (7) (47%)

3 0 1 1 2 0 1 0 (7) (8) (58%)

4 0 2 1 5 1 1 (14) (15) (52%)

1 0 1 0 1 0 3 (20.0%)

2 0 1 0 0 0 3 (25%)

3 0 2 0 1 0 6 (22%)

32 11 (34.3%) 15 (3 days–55 months)

*% in related drug group. % in splenectomized patients of related drug group. ‡ % in non-splenectomized patients of related drug group. § Percentage of patients who had side effects in the related drug group. n1 total number of the patients who had side effects in the related drug group. n2 total number of side effects in n1. †

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than 30 mg/kg/g and 75% of patients taking deferiprone had a dose of equal or greater than 75 mg/ kg/g at the time of discontinuation. The aforementioned studies reported a side-effect rate of up to 40% for both drugs, which was found to be higher in our study. This may result from increasing drug dose, as well as increased awareness and more thorough investigation of side effects. Although our study showed that deferasirox decreased ferritin more than deferiprone does, one should take into account that deferasirox was used longer (36 vs. 28 months; P = 0.007) and deferiprone was discontinued more frequently. Hence, there was no significant difference between deferasirox and deferiprone in terms of ferritin decrease when patients discontinuing deferiprone in the first year were excluded (870 vs. 811 ng/ml, respectively; P = 0.5). Few studies have suggested that the risk of toxicity with deferoxamine is increased among patients with lower iron burdens, yet it is less clear whether similar toxicity is seen with deferasirox or deferiprone at low levels of iron burden.16,17 In contrast, our study showed that a high level of ferritin is significantly associated with discontinuation of the oral chelator. Although this condition may be interpreted as ferritin was higher and larger doses were required, the last doses were not significantly different between patients who discontinued and those who did not (Tables 1 and 2). There is a need for studies with larger sample size and more homogenous groups to elucidate the relationship between higher ferritin levels and discontinuation rate. T2* cardiovascular magnetic resonance is a noninvasive technique that provides assessment of myocardial iron content and its usefulness in monitoring iron chelation has been extensively proved. Despite robust data in literature on increased T2* level with deferiprone and defroxamine combination, such an effect of deferasirox has not been clearly reported so far.18–20 Our study demonstrated that both deferasirox and combination therapy yielded a statistically nonsignificant increase in T2* level by about 3 ms after a mean of 1-year therapy. The magnitude of improvement in T2* level may be reassessed following a longer therapy. The most common side effect leading to discontinuation of the drug was gastrointestinal causes. In deferasirox users, gastrointestinal disturbances caused interruption of therapy in 16 patients (15%) while subsequent discontinuation in seven, owing to serious side effects (ulcer, diarrhea, nausea) which decrease their oral intake. Detection of ulcers complicated by gastrointestinal bleeding in two of these patients indicates that gastrointestinal complaints should be questioned in detail. Despite similar gastrointestinal system (GIS) complaints were observed in deferiprone users,

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they discontinued the drug more frequently (7/16, 43% for deferasirox vs. 8/11, 72% for deferiprone). Deferasirox and its iron complex are primarily excreted in the bile and feces and subsequent enterohepatic recycling is likely to occur. Thus, enterohepatic circulation may explain GIS side effects of the drug. However, the exact mechanism for oral chelators by which gastrointestinal side effects occur is not fully understood. The drug was discontinued in half of those who experienced visual side effects, whereas the drug was not discontinued in patients with auditory side effects, although a higher percentage of auditory side effects compared to the literature was detected.21 In circumstances when hearing is affected in oral chelators, a more flexible follow up followed by dose reduction may be recommended; however, studies with larger sample size are required to clarify this issue. Spleen is one of the largest iron depots of the body and splenectomy might result in a diverse effect on iron balance and influence the pharmacokinetic profiles of chelators. Cohen et al. reported that the patients who had been splenectomized had a significantly greater reduction in serum ferritin level than those who had not, probably as a result of decreased transfusional iron intake.22 In patients taking deferasirox who had had splenectomy operation, ferritin decreased significantly while discontinuation rate was increased in our study. The decrease in iron overload would result in expected reduced clinical complications due to iron overload; however, increased discontinuation rate of deferasirox might reduce this positive effect. Bruin et al. 23 reported that, in the albino animals, after intravenous administration of deferasirox, the tissue distribution was primarily intravascular; however, up to 8 hours postdose, the highest exposure values were observed in bile, liver, and kidney substructures; thus, at 168 hours postdose, it was detected in the kidney cortex, bone marrow, lung, liver, and spleen at lower exposures. Removal of the spleen reduces the amount of tissue that deferasirox will distribute, which might increase the exposure of the tissues to deferasirox leading to increased toxicity. Deferasirox is a lipophilic chelator, forming a chelator:iron complex and it may cause the decompartmentalization of copper, zinc, and some other metals, and possibly toxicities associated with the regulation of metal-containing enzymes and other dependent biomolecules.24 Deferiprone chelates iron and then the water-soluble deferiprone–iron complexes that are formed are excreted in the urine, together with the inactive form the glucuronide metabolite.25 Limenta et al. 8 reported that urinary excretion of deferiprone glucuronide is decreased in splenectomized thalassemic patients,


therefore it can be speculated that splenectomized patients would have more toxicities. However, in our study there was not any significant difference in terms of the frequency of side effects. Furthermore, non-splenectomized deferiprone users had higher discontinuation rates and interestingly, neutropenia was more common in patients with intact spleens. This was consistent with the study of Cohen et al. 26 in that neutropenia occurred predominantly in nonsplenectomized patients. Our study has some limitations. First, the patients’ ages were in a wide range. In addition, higher iron burden in older patients than younger patients may complicate the determination of the influence of chelators on side effects because of concerns about the relationship between dosage and side effects. Second, despite clinical problems associated with TM primarily stems from iron overload, multifactorial causes are also operational and resulting issues may not be entirely chelator-related. Third, assessment of the efficacy of chelator in reducing iron burden was limited to serum ferritin analysis and partially to changes in cardiac T2* level in this study, as serum ferritin levels can be influenced by inflammatory processes.27 Fourth, since patients taking combination therapy with deferoxamine were also included in the study to increase the number of patients taking deferiprone, it should be taken into account that deferoxamine may have contributed to the effect in these patients. In conclusion, our retrospective evaluation of TM patients using oral chelators showed that oral chelators are effective in reducing iron overload regarding ferritin level and partially in cardiac T2* value. However, in our study side effects and discontinuation rates were unexpectedly high and close follow up of TM patients using oral chelators should be carefully done. The variability in rate of side effects and drug discontinuation in spelenectomized patients using oral chelators suggests that spleen may have a role in pharmacokinetics of these drugs, as well.

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