Improved efficacy and tolerability of oral deferasirox by twice-daily dosing for patients with transfusion-dependent β-thalassemia

Authors

  • Hsiu-Hao Chang MD,

    1. Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
    2. Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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  • Meng-Yao Lu MD,

    1. Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
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  • Yu-Mei Liao MD,

    1. Department of Pediatrics, Kaohsiung Medical University Hospital, Kaoshiung, Taiwan
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  • Pei-Chin Lin MD,

    1. Department of Pediatrics, Kaohsiung Medical University Hospital, Kaoshiung, Taiwan
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  • Yung-Li Yang MD,

    1. Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
    2. Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
    3. Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
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  • Dong-Tsamn Lin MD,

    1. Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
    2. Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
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  • Shyh-Shin Chiou MD,

    1. Department of Pediatrics, Kaohsiung Medical University Hospital, Kaoshiung, Taiwan
    2. Kaohsiung Medical University, Kaoshiung, Taiwan
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  • Shiann-Tarng Jou MD, PhD,

    1. Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
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  • Kai-Hsin Lin MD,

    1. Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
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  • Tai-Tsung Chang MD

    Corresponding author
    1. Department of Pediatrics, Kaohsiung Medical University Hospital, Kaoshiung, Taiwan
    2. Kaohsiung Medical University, Kaoshiung, Taiwan
    • Division of Hematology/Oncology, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No.100, Tzyou 1st Rd., Kaohsiung 807, Taiwan.
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  • Conflict of interest: Nothing to declare.

Abstract

Background

Deferasirox is an oral iron-chelating agent taken once-daily by patients with transfusion-dependent iron overload. However, some patients are unresponsive or unable to tolerate once-daily deferasirox. The current study evaluated whether twice-daily deferasirox treatment showed increased efficacy or tolerability in unresponsive or intolerant patients.

Procedure

Patients from two Taiwanese hospitals with transfusion-dependent β-thalassemia, including those who showed increasing serum ferritin levels for six consecutive months, with at least one level >2,500 ng/dl, while treated with >30 mg/kg/day of once-daily deferasirox (unresponsive) or developed deferasirox-related adverse events (AEs) at the dosage required to maintain the iron burden balance (intolerant) and were treated twice-daily with the same total daily dose of deferasirox since 2008, were enrolled in the study and evaluated retrospectively by medical record review.

Results

Eighteen patients were included for analysis. A statistically significant median decrease in serum ferritin levels was detected in the 11 unresponsive patients after 6 months of continuous twice-daily deferasirox treatment. Five out of the seven intolerant patients experienced either no deferasirox-related AEs or less severe AEs. The 12 patients from both groups (11 unresponsive, 1 intolerant) who received continuous twice-daily deferasirox for 6 months showed a mild but significant median increase in serum creatinine levels.

Conclusions

Twice-daily deferasirox dosing is effective in iron chelation and improves tolerability in transfusion-dependent β-thalassemia patients who are unresponsive to or intolerant of once-daily deferasirox. Future studies with greater patient numbers will be required to confirm the results reported herein. Pediatr Blood Cancer 2011;56:420–424. © 2010 Wiley-Liss, Inc.

INTRODUCTION

Deferasirox is a once-daily oral iron chelator that represents a new class of tridentate iron chelators 1. Deferasirox is currently approved in many countries for the treatment of patients over 2 years of age with transfusion-dependent iron overload, and its once-daily administration leads to high patient satisfaction and compliance 2. Previous phase 2 and 3 trials involving deferasirox treatment have shown that a dose of between 20 and 30 mg/kg/day generally produces a net negative iron balance 1, 3, 4. Doses greater than 30 mg/kg/day were not recommended in the prescribing information when deferasirox was first approved 5, 6. However, a recent retrospective study demonstrated that doses of deferasirox greater than 30 mg/kg/day are safe and more effective than a lower dose in reducing the iron burden in some patients with transfusion-dependent iron overload 5. The current maximum FDA-approved dose of deferasirox has been increased to 40 mg/kg/day in the U.S. 6.

In Taiwan, patients with transfusion-dependent iron overload, most of whom had β-thalassemia, began to join clinical trials of deferasirox in 2005, and deferasirox was approved and became commercially available in 2007. A small portion of patients, especially heavily iron-loaded patients, could not achieve adequate iron chelation and a negative iron balance, even when receiving deferasirox doses exceeding 30 mg/kg/day (poor response). Furthermore, some patients experienced deferasirox-related adverse events (AEs) at the dose required to maintain the iron burden balance (intolerance). If AEs are managed by decreasing the dose of deferasirox or interrupting treatment, these patients will not be able to achieve adequate iron chelation and maintain a negative iron balance during their regular blood transfusions. However, most of them still preferred to continue deferasirox treatment due to the convenience in taking this drug. Although the reported average half-life for deferasirox is between 11 and 16 hr 2, one previous study has shown that the half-life of deferasirox may decrease to 7 hr in some patients 7, and this may decrease the total effective time of drug coverage. In addition, some deferasirox AEs may be dose-dependent 4 and related to peak drug levels. In the current study, we hypothesized that a twice-daily deferasirox treatment regimen would result in reduced peak drug levels and achieve a longer period during which concentrations remained at effective levels. Therefore, in 2008, we began to allow patients to take deferasirox twice-daily using the same total daily dose that was previously given once-daily. The aim of the current study was to evaluate the efficacy and tolerability of a twice-daily deferasirox dosing schedule among patients with transfusion-dependent β-thalassemia who were unresponsive or intolerant to once-daily deferasirox treatment.

METHODS

Study Design and Patient Enrollment

Twice-daily dosing of deferasirox has been used as an alternative therapy to once-daily dosing since June 2008 at the Kaohsiung Medical University Hospital and since January 2009 at the National Taiwan University Hospital. The current retrospective study analyzed patients with transfusion-dependent β-thalassemia who had a poor response or were intolerant to once-daily deferasirox treatment and were treated twice-daily with the same total daily dose of deferasirox as an alternative therapy. These patients received regular blood transfusions (10–15 ml packed erythrocytes/kg body weight) every 2–4 weeks to maintain a hemoglobin level of at least 9.5 g/dl before each transfusion.

The definition of a poor response to deferasirox included a rising trend of serum ferritin levels for six consecutive months, with at least one level >2,500 ng/dl, while on a deferasirox dosage of >30 mg/kg/day. The definition of intolerance to deferasirox included the development of deferasirox-related AEs at the dosage required to maintain the iron burden balance. Patients who had previously exhibited a poor response to once-daily deferasirox and continuously received twice-daily dosing for at least 6 months were enrolled in the efficacy analysis of iron chelation. Patients who had previously exhibited intolerance to once-daily deferasirox treatment and received twice-daily dosing as an alternative therapy were enrolled in the tolerability analysis for deferasirox treatment. Clinical data from these patients were obtained retrospectively by medical record review, and this study was approved by the Institutional Review Board of the two participating hospitals.

Assessment

Serum ferritin, liver enzymes, pancreatic enzymes, and serum creatinine levels were measured monthly in the study patients and any AEs related to deferasirox treatment were recorded at every clinic visit. Iron chelation efficacy was evaluated based on monthly changes in serum ferritin levels. The AEs related to deferasirox were evaluated and graded according to the Common Terminology Criteria for Adverse Events (U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute, Bethesda, MD, USA). Furthermore, tolerability of the alternative regimen was determined by comparing the severity of AEs associated with once-daily deferasirox treatment to those associated with twice-daily deferasirox treatment.

Statistical Analyses

Continuous variables are summarized by descriptive statistics, including the median and range. Categorical variables are presented as the number and percentage in each category. Comparisons of serum ferritin and creatinine levels between baseline (i.e., before twice-daily dosing) and after the last measurement following twice-daily dosing were determined using a paired Wilcoxon test. A statistically significant difference was defined as a P < 0.05.

RESULTS

Patient Characteristics

Of the 82 patients with transfusion-dependent β-thalassemia who had previously received once-daily deferasirox for iron chelation therapy, 25 (30.5%) were switched to twice-daily deferasirox at the same total daily dosage. Eighteen of the 25 patients (22%) received twice-daily deferasirox because of a poor response to the once-daily dose, and 7 of the 25 patients (8%) received twice-daily deferasirox because of intolerance to the once-daily dose. Of the 18 patients who received twice-daily deferasirox due to a poor response, 4 were excluded from the efficacy analysis because of poor compliance and discontinuation of twice-daily dosing, and three were excluded because they had received twice-daily dosing for <6 months at the time of the analysis. Therefore, only 11 patients were eligible for the efficacy analysis. The general clinical characteristics of these 11 patients are provided in Table I.

Table I. Demographic Data for the 11 Patients Included in the Analysis of Iron Chelation Efficacy Associated With Twice-Daily Deferasirox Dosing
VariablePatients (n = 11)
  1. DM, diabetes mellitus.

Age (years)
 12–207
 21–302
 31–352
Gender
 Male6
 Female5
Hepatitis C
 Yes3
 No8
DM
 Yes1
 No10
Baseline median serum ferritin levels (range), ng/dl, before twice-daily deferasirox3,628 (2,572–7,260)

Changes in Serum Ferritin Levels

Among the 11 patients who met the requirements for the efficacy analysis, serum ferritin levels at baseline, immediately prior to initiating twice-daily dosing, ranged from 2,572 to 7,260 ng/dl (median, 3,628 ng/dl; Table I). During the 6 months of twice-daily dosing, the serum ferritin levels decreased relative to baseline values in all 11 patients. The magnitude of the reduction in serum ferritin levels was <500 ng/dl in one patient, between 500 and 1,000 ng/dl in one patient, between 1,000 and 2,000 ng/dl in seven patients, and between 2,000 and 3,000 ng/dl in two patients. The distribution of serum ferritin levels in these 11 patients at baseline and after twice-daily deferasirox dosing for 6 months is shown in Figure 1. The median serum ferritin levels in the 11 patients at baseline and during the 6 months of twice-daily deferasirox dosing are shown in Figure 2. In the 11 patients, the median serum ferritin level decreased from 3,628 ng/dl at baseline to 2,185 ng/dl after 6 months of treatment, and there was a statistically significant median decrease in serum ferritin levels of 1,443 ng/dl (P = 0.003, paired Wilcoxon test). The median change in serum ferritin levels after twice-daily deferasirox treatment for 6 months was −39.8% relative to baseline levels. The total daily dose of deferasirox at baseline and after 6 months of twice-daily deferasirox treatment remained the same: both were 36.4 mg/kg/day.

Figure 1.

Distribution of serum ferritin levels for the 11 patients included in the analysis of iron chelation efficacy at baseline and after twice-daily deferasirox dosing for 6 months.

Figure 2.

Serum ferritin levels for the 11 patients included in the analysis of iron chelation efficacy with twice-daily deferasirox dosing. Median values are connected, and the vertical bars represent the 10th and 90th percentiles.

Improved Tolerability

Of the seven patients who were switched to twice-daily deferasirox treatment because they were intolerant to once-daily dosing, three had elevated liver enzyme levels, two had arthralgias, one had gastrointestinal (GI) pain, and one had pancreatitis in which only elevated serum amylase levels were noted (Table II). After the change from once-daily to twice-daily dosing was made, five out of the seven patients (71.4%) either had no deferasirox-related AEs or had deferasirox-related AEs that were reduced in severity. The onset of improvement in these AEs generally occurred after 1–2 months. With respect to the changes in serum ferritin levels for these seven patients, only two patients had increased serum ferritin levels (Subjects 1 and 5; Table II), and the remaining five patients had either decreased or similar serum ferritin levels (Table II) after a variable duration of twice-daily deferasirox.

Table II. Demographic Data and Outcomes for the Seven Patients Who Received Twice-Daily Deferasirox Due To Intolerance to Previous Once-Daily Deferasirox
Subject no.GenderAge (years)Hepatitis BHepatitis CDMAdverse events (AEs)Severity of AEsDosage (mg/kg/day)OutcomesTotal duration (months)aSerum ferritin levels (ng/dl)b
  • DM, diabetes mellitus.

  • a

    Total duration of twice-daily deferasirox at the time of analysis;

  • b

    Serum ferritin levels at baseline and the time of analysis.

1Male24NoNoNoArthralgiaGrade 215Disappeared after twice-daily deferasirox for 1 month81,357–1,769
2Female28NoYesYesArthralgiaGrade 230Improved to Grade 1 after twice-daily deferasirox for 2 months3566–488
3Male24NoNoNoElevated liver enzyme levelsGrade 125Returned to normal after twice-daily deferasirox for 1 month31,104–575
4Male25NoYesNoElevated liver enzyme levelsGrade 140Returned to normal after twice-daily deferasirox for 3 months36,246–3,988
5Female32NoYesNoGastrointestinal pain (GI upset)Grade 230Disappeared after twice-daily deferasirox for 1 month55,860–6,016
6Male28YesNoNoElevated liver enzyme levelsGrade 240Not improved34,318–2,766
7Female18NoNoNoPancreatitis (only elevated serum amylase levels)Grade 220Not improved5864–816

Safety Profile

After 2 months of treatment, one of the 25 patients receiving twice-daily deferasirox had serum creatinine levels that were elevated above the normal range (1.1 mg/dl at baseline to 1.5 mg/dl at 2 months; normal range, <1.3 mg/dl). This patient's creatinine levels returned to normal after the total deferasirox daily dose was decreased from 40 to 35 mg/kg/day. No new AEs were detected in the remaining 24 patients following the change to twice-daily dosing. Furthermore, no serious AEs were observed while the 25 patients were receiving twice-daily deferasirox treatment. When we analyzed the serum creatinine levels in the 12 patients who continuously received twice-daily deferasirox for at least 6 months, including 11 patients from the iron chelation efficacy analysis, and 1 patient (Subject 1, Table II) who was intolerant to once-daily dosing, we found that the serum creatinine levels were all in the normal range after 6 months of twice-daily treatment. However, although serum creatinine levels were within the normal range, there was a statistically significant median increase in serum creatinine levels of 0.05 mg/dl (P = 0.04, paired Wilcoxon test) in this group of 12 patients after 6 months of twice-daily dosing. The median serum creatinine levels for this group of 12 patients over the 6-month period of twice-daily deferasirox treatment are shown in Figure 3.

Figure 3.

Serum creatinine levels for the 12 patients (11 unresponsive and 1 intolerant) who continuously received twice-daily deferasirox dosing for at least 6 months. Median values are connected, and the vertical bars represent the 10th and 90th percentiles.

DISCUSSION

Patients with transfusion-dependent β-thalassemia require a higher dose of deferasirox for adequate iron chelation than those with other anemias because of the high iron burden and transfusion requirements in this patient population 8. Taher et al. 5 reported a retrospective pooled analysis of 264 patients with anemias of different etiologies and showed that 85.2% of the patients in the study who received deferasirox in a dose of greater than 30 mg/kg/day had transfusion-dependent β-thalassemia. Although the escalation of deferasirox to doses greater than 30 mg/kg/day was safe and effectively decreased serum ferritin levels in most of the patients whose serum levels had not been adequately controlled, a small portion of the 264 high-dose patients discontinued deferasirox permanently due to an insufficient decrease in serum ferritin levels (n = 19) or drug-related AEs (n = 4). Chirnomas et al. 6 also reported that some patients with transfusion-dependent iron overload have an inadequate iron chelation response to once-daily deferasirox treatment with doses greater 30 mg/kg/day. Therefore, it is reasonable to expect that a small percentage of patients with transfusion-dependent iron overload will have a poor response or will be intolerant to once-daily deferasirox treatment; however, the percentage of patients in these categories may vary due to differences in clinical judgment and differences in the criteria used to establish a poor response or intolerance to deferasirox among different patient cohorts and geographic areas.

The current study shows that twice-daily deferasirox treatment with divided doses of the standard once-daily deferasirox regimen effectively improves iron chelation efficacy and tolerability among patients with transfusion-dependent β-thalassemia who were not responsive to or were intolerant of once-daily deferasirox dosing. Of the 11 patients included in the iron chelation efficacy analysis, 9 showed a reduction in serum ferritin levels of >1,000 µg/L and only 1 patient had a reduction in the serum ferritin level of <500 µg/L after 6 months of treatment. Even among the seven patients who received twice-daily deferasirox due to intolerance of once-daily dosing, most showed an elimination or reduction in deferasirox-related AEs while still achieving iron chelation efficacy. However, drug compliance for patients receiving twice-daily deferasirox should be monitored carefully. There were four patients (16%) who began receiving twice-daily deferasirox but eventually discontinued this dosage schedule and returned to once-daily dosing because of poor compliance.

Plasma deferasirox levels were not measured in the current study. In the initial study of the pharmacokinetic profile for deferasirox, the observed half-life of 11–19 hr supported a once-daily dosing regimen as deferasirox plasma levels were maintained within the therapeutic range over a 24-hr period and provided continuous iron chelation coverage 9. However, differences in the pharmacokinetics profiles among patients receiving deferasirox were reported in the first phase I study of deferasirox, particularly in patients prescribed a high dose of 40 mg/kg/day; these patients had highly variable deferasirox plasma levels and net iron excretion in response to deferasirox administration 10. Differences in once-daily deferasirox pharmacokinetics that may lead to differences in systemic drug exposure and inadequate or poor clinical response among patients with transfusion-dependent iron overload have also been reported 6. Dividing the once-daily deferasirox dose into two smaller daily doses should have pharmacokinetic advantages because peak concentrations will be lower and may be associated with decreased intolerance, and trough concentrations should be higher and increase the period during which drug concentrations are at efficacious levels. These pharmacokinetic benefits were discussed by Otto-Duessel et al. 11 in a study that compared twice-daily dosing with once-daily dosing of deferasirox in a gerbil model of iron overload. In that study, the ratio of cardiac to hepatic iron content was lower, and the liver water content was unchanged in the twice-daily dosing group. The results of that study provide evidence that twice-daily dosing with deferasirox provides broader suppression of non-transferrin-bound iron species and less toxicity relative to once-daily dosing 11. Taken together with these findings, the effects of twice-daily deferasirox dosing in the current study may be associated with decreased peak drug levels and increased systemic drug exposure, which may in turn lead to improved drug tolerability and iron chelation efficacy for patients who were previously unresponsive or intolerant to once-daily deferasirox dosing. Discovery of the precise mechanism(s) underlying the effects of twice-daily deferasirox for these patients will require further study.

Twice-daily deferasirox dosing was well tolerated among the patients in the current study. Although there was a statistically significant median increase in serum creatinine levels in patients who continuously received twice-daily deferasirox for 6 months, the level of significance was borderline (P = 0.04) and the median increase in serum creatinine was relatively low (0.05 mg/dl). Only one patient had elevated serum creatinine levels above the normal range, and they were effectively lowered through dose adjustment. With the exception of this patient, there were no other new or even serious AEs among the other patients who received twice-daily deferasirox treatment. Collectively, the results of the current study provide evidence that it is generally safe for patients with transfusion-dependent β-thalassemia to receive twice-daily deferasirox, although the serum creatinine levels of these patients should be closely monitored.

The limitations of the current study include the retrospective nature of the analysis and the relatively small number of patients. The response rate to twice-daily deferasirox of patients who did not respond to or tolerate once-daily deferasirox was not determined in this study. To establish a complete safety profile for patients receiving twice-daily deferasirox, a larger patient population and a longer follow-up time will be required. However, the results of the current study suggest that twice-daily deferasirox treatment should be attempted for patients with transfusion-dependent iron overload who are either unresponsive to or intolerant of once-daily deferasirox and prefer not to switch to a different iron-chelating agent. Taken together, the results of the current study could serve as the basis for a larger, prospective study to further evaluate the efficacy of twice-daily deferasirox treatment.

In conclusion, the results of the current study show that twice-daily deferasirox treatment provides effective iron chelation and improves tolerability in patients with transfusion-dependent β-thalassemia who are unresponsive or intolerant of once-daily dosing. This treatment approach may serve as an alternative therapeutic option for these patients. Close monitoring of serum creatinine levels among patients receiving twice-daily deferasirox is essential. An understanding of the mechanism(s) underlying the effects of twice-daily deferasirox for these patients will require further study.

Acknowledgements

We thank all of the patients and their parents for their participation in this study. We also acknowledge the Taiwan Thalassemia Association and the Kaohsiung Thalassemia Association in Taiwan for data collection and management. This work was supported in part by a grant from the National Taiwan University Hospital (NTUH 95-M19 to H.-H.C.).

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