Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years' follow-up

Abstract Patients with β-thalassemia require lifelong iron chelation therapy from early childhood to prevent complications associated with transfusional iron overload. To evaluate long-term efficacy and safety of once-daily oral iron chelation with deferasirox, patients aged ≥ 2 years who completed a 1-year, phase 3, randomized trial entered a 4-year extension study, either continuing on deferasirox (deferasirox cohort) or switching from deferoxamine to deferasirox (crossover cohort). Of 555 patients who received ≥ 1 deferasirox dose, 66.8% completed the study; 43 patients (7.7%) discontinued because of adverse events. In patients with ≥ 4 years' deferasirox exposure who had liver biopsy, mean liver iron concentration significantly decreased by 7.8 ± 11.2 mg Fe/g dry weight (dw; n = 103; P < .001) and 3.1 ± 7.9 mg Fe/g dw (n = 68; P < .001) in the deferasirox and crossover cohorts, respectively. Median serum ferritin significantly decreased by 706 ng/mL (n = 196; P < .001) and 371 ng/mL (n = 147; P < .001), respectively, after ≥ 4 years' exposure. Investigator-assessed, drug-related adverse events, including increased blood creatinine (11.2%), abdominal pain (9.0%), and nausea (7.4%), were generally mild to moderate, transient, and reduced in frequency over time. No adverse effect was observed on pediatric growth or adolescent sexual development. This first prospective study of long-term deferasirox use in pediatric and adult patients with β-thalassemia suggests treatment for ≤ 5 years is generally well tolerated and effectively reduces iron burden. This trial was registered at www.clinicaltrials.gov as #NCT00171210.

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LONG-TERM EFFECTIVENESS, SAFETY, AND TOLERABILITY OF TWICE-DAILY DOSING WITH DEFERASIROX IN CHILDREN WITH TRANSFUSION-DEPENDENT THALASSEMIAS UNRESPONSIVE TO STANDARD ONCE-DAILY DOSING

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2021.065 ◽

2021 ◽

Vol 13 (1) ◽

pp. e2021065

Author(s):

Jassada Buaboonnam ◽

Chayamon Takpradit ◽

Vip Viprakasit ◽

Nattee Narkbunnam ◽

Nassawee Vathana ◽

...

Keyword(s):

Safety Profile ◽

Chelation Therapy ◽

Iron Concentration ◽

Iron Chelation ◽

Liver Iron ◽

Once Daily ◽

Treatment Interruptions ◽

Inadequate Responders

Background: Patients with transfusion-dependent thalassemia (TDT) risk iron overload and require iron chelation therapy. Salvage therapy is warranted for patients demonstrating poor chelation responses. Patients and methods: We retrospectively studied the serum-ferritin (SF) and liver-iron-concentration (LIC) outcomes of patients with TDT treated with twice-daily dosing of deferasirox (TDD-DFX) for > 24 months, after failing to respond to once-daily deferasirox (OD-DFX). Results: We enrolled 22 patients (14 males and 8 females; median age, 9.2 [3–15.5] years). The median erythron transfusion was 216 (206–277) ml/kg/year. The median TDD-DFX treatment period was 30 (24–35) months. Before initiating TDD-DFX, the median SF level was 2,486 (1,562–8,183) ng/ml, while the median LIC was 6.5 (3.2–19) mg/g dry wt. There were 18 responders (81.8%) and 4 nonresponders. The median SF-level change was -724 (-4 916 to 1,490) ng/mL. The median LIC change was -2.14 (-13.7 to 6.8) mg/g dry wt. The 1-year and end-of-study SF levels and LICs were statistically significant (SF, P = 0.006/0.005; and LIC, 0.006/0.005, respectively). There were no treatment interruptions secondary to adverse events. In the follow-up of the TDD-DFX-responder group, 11 of the 18 had a reduced dose, whereas the remaining 7 continued with the same dose. Conclusions: TDD-DFX appears to be an alternative treatment approach for patients refractory to OD-DFX, with a favorable long-term safety profile. Further studies with larger groups and pharmacogenetic analyses of inadequate responders are warranted to better determine the efficacy and safety profile of TDD-DFX.

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SEVERE LIVER IRON CONCENTRATIONS (LIC) IN 24 PATIENTS WITH Β-THALASSEMIA MAJOR: CORRELATIONS WITH SERUM FERRITIN, LIVER ENZYMES AND ENDOCRINE COMPLICATIONS

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2018.062 ◽

2018 ◽

Vol 10 ◽

pp. e2018062 ◽

Cited By ~ 3

Author(s):

Vincenzo De Sanctis

Keyword(s):

Iron Overload ◽

Adrenal Insufficiency ◽

Serum Ferritin ◽

Chelation Therapy ◽

Ferritin Level ◽

Iron Chelation ◽

Dry Weight ◽

Thalassemia Major ◽

Liver Iron

Abstract. Introduction: Chronic blood transfusion is the mainstay of care for individuals with β-thalassemia major (BTM). However, it causes iron-overload that requires monitoring and management by long-term iron chelation therapy in order to prevent endocrinopathies and cardiomyopathies, that can be fatal. Hepatic R2 MRI method (FerriScan®) has been validated as the gold standard for evaluation and monitoring liver iron concentration (LIC) that reflects the total body iron-overload. Although adequate oral iron chelation therapy (OIC) is promising for the treatment of transfusional iron-overload, some patients are less compliant with it and others suffer from long-term effects of iron overload. Objective: The aim of our study was to evaluate the prevalence of endocrinopathies and liver dysfunction, in relation to LIC and serum ferritin level, in a selected group of adolescents and young adult BTM patients with severe hepatic iron overload (LIC from 15 to 43 mg Fe/g dry weight). Patients and Methods: Twenty-four selected BTM patients with severe LIC, due to transfusion-related iron-overload, followed at the Hematology Section, National Center for Cancer Care and Research, Hamad Medical Corporation of Doha (Qatar), from April 2015 to July 2017, were retrospectively evaluated. The prevalence of short stature, hypogonadism, hypothyroidism, hypoparathyroidism, impaired fasting glucose (IFG), diabetes, and adrenal insufficiency was defined and assessed according to the International Network of Clinicians for Endocrinopathies in Thalassemia (ICET) and American Diabetes Association criteria. Results: Patients have been transfused over the past 19.75 ± 8.05 years (ranging from 7 to 33 years). The most common transfusion frequency was every 3 weeks (70.8%). At the time of LIC measurements, the mean age of patients was 21.75 ± 8.05 years, mean LIC was 32.05 ± 10.53 mg Fe/g dry weight (range: 15 to 43 mg Fe/g dry weight). Their mean serum ferritin level was 4,488.6 ± 2,779 µg/L. The overall prevalence of growth failure was 26.1% (6/23), IFG was 16.7% (4/24), sub-clinical hypothyroidism was 14.3% (3/21), hypogonadism was 14.3% (2/14), diabetes mellitus was 12.5% (3/24), and biochemical adrenal insufficiency was 6.7% (1/15). The prevalence of hepatitis C positivity was 20.8% (5/24). No case of clinical hypothyroidism, adrenal insufficiency or hypoparathyroidism was detected in this cohort of patients. The prevalence of IFG impaired fasting glucose was significantly higher in BTM patients with very high LIC (>30 mg Fe/g dry liver) versus those with lower LIC (p = 0.044). LIC was correlated significantly with serum ferritin levels (r = 0.512; p = 0.011), lactate dehydrogenase (r = 0.744; p = 0.022) and total bilirubin (r = 0.432; p = 0.035). Conclusions: A significant number of BTM patients, with high LIC and endocrine disorders, still exist despite the recent developments of new oral iron chelating agents. Therefore, physicians’ strategies shall optimize early identification of those patients in order to optimise their chelation therapy and to avoid iron-induced organ damage. We believe that further studies are needed to evaluate if serial measurements of quantitative LIC may predict the risk for endocrine complications. Until these data are available, we recommend a close monitoring of endocrine and other complications, according to the international guidelines.

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Lack of Correlation between Serum Ferritin and Liver Iron Concentration in Beta-Zero Thalassemia Intermedia.

Blood ◽

10.1182/blood.v104.11.3620.3620 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3620-3620 ◽

Cited By ~ 1

Author(s):

Renzo Galanello ◽

Nicolina Giagu ◽

Susanna Barella ◽

Liliana Maccioni ◽

Raffaella Origa

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Regulatory Protein ◽

Iron Concentration ◽

Iron Chelation ◽

Dry Weight ◽

Thalassemia Major ◽

Thalassemia Intermedia ◽

Liver Iron Concentration ◽

Liver Iron

Abstract Serum ferritin and liver iron concentration (LIC) are the most commonly used methods for assessment of iron overload in thalassemia. While in patients with thalassemia major a significant correlation has been found between these two parameters, data are lacking in patients with thalassemia intermedia. In this study we measured the serum ferritin and LIC in 22 adult patients with beta-zero thalassemia intermedia never transfused (14 patients) or sporadically transfused, i.e. less than 10 units in total (8 patients), who maintained a mean hemoglobin of 8.8 ± 1.1 g/dl. Serum ferritin levels were measured by an automated chemiluminescence immunoassay analyzer, whereas LIC was determined by atomic absorption in liver biopsies. We compared the results obtained in those patients with those obtained in 22 regularly transfused (mean annual Hb = 11.3 ± 0.3 g/dl) and iron chelated thalassemia major patients, matched by sex, age and liver iron concentration. We also determined serum erythropoietin (s-epo) and serum transferrin receptor (s-TfR) in a cohort of the two patient groups (12 thalassemia intermedia; 15 thalassemia major). Mean LIC was 11.3 ± 6 mg/g dry weight tissue in thalassemia intermedia, and 11.8 ± 7 mg/g d.w. in thalassemia major group. Mean serum ferritin (at least 2 determinations from each patient within ± 2 months of liver biopsy) was 627 ± 309 ng/ml in thalassemia intermedia and 2748 ± 2510 ng/ml in thalassemia major. The difference was statistically significant (p = 0.0001). LIC was weakly correlated with serum ferritin in thalassemia major patients (r2=0.46; p=0.001) and uncorrelated in patients with thalassemia intermedia (r2=0.04; p=0.37) (Figure). S-epo and s-TfR were significantly higher in thalassemia intermedia than in thalassemia major [s-epo 467 ± 454 mU/ml versus 71 ± 44 mU/ml (p<0.001); s-TfR 43 ± 13 mU/ ml versus 13 ± 6 mU/ml (p<0.0001)]. The discrepancy between LIC and serum ferritin in thalassemia intermedia patients may be due to the higher levels of s-epo (secondary to anemia) in those patients, which through the iron regulatory protein 1 determine an up-regulation of s-TfR and a repression of ferritin translation (Weiss et al 1997). The mechanism of iron overload may also be mediated by hepcidin, whose synthesis could be suppressed as a consequence of anemia. The observation reported has important implications for iron chelation in patients with thalassemia intermedia. In such patients serum ferritin levels have little value for the monitoring of iron overload. Figure Figure

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Deferasirox (Exjade®) in Pediatric Patients with β-Thalassemia: Update of 4.7-Year Efficacy and Safety from Extension Studies

Blood ◽

10.1182/blood.v112.11.3883.3883 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3883-3883 ◽

Cited By ~ 3

Author(s):

Antonio Piga ◽

Gian Luca Forni ◽

Antonis Kattamis ◽

Christos Kattamis ◽

Yesim Aydinok ◽

...

Keyword(s):

Pediatric Patients ◽

Iron Concentration ◽

Safety Data ◽

Iron Chelation ◽

Dose Titration ◽

Efficacy And Safety ◽

Liver Iron ◽

Long Term Treatment ◽

Median Change

Abstract Background: As pediatric patients with β-thalassemia will require lifelong iron chelation therapy, it is important to evaluate the long-term efficacy, safety and growth during treatment with any iron chelator. This analysis presents cumulative efficacy and safety data from a cohort of pediatric patients treated with the once-daily, oral chelator deferasirox during two 1-year core and 4-year extension trials. Methods: β-thalassemia patients aged 2–<16 years with transfusional iron overload were enrolled in two extension studies (107E and 108E) evaluating the long-term safety, tolerability and efficacy (by serum ferritin [SF] levels) of deferasirox; only patients who received deferasirox from the beginning of the core trial are included in this analysis. Deferasirox doses in the extension trials were initially based on end-of-core liver iron concentration, and were adjusted according to trends in SF levels. Efficacy was monitored by monthly SF levels; safety was assessed by the incidence and type of adverse events (AEs) and laboratory parameters. Results: 168 patients (153 patients from study 107 and 15 from study 108) aged 2–<6 (n=30), 6–<12 (n=74) and ≥12–<16 (n=64) years entered the extensions. To date, patients have received deferasirox for a median of 56.1 months (4.7 years) at an average daily dose of 22.5 ± 6.6 mg/kg/day. Mean iron intake during treatment was 0.4 ± 0.1 mg/kg/day. Mean actual dose at month 3 was 19.8 ± 8.8 mg/kg/day, which increased to 28.3 ± 7.3 mg/kg/day by month 54. Median SF levels at baseline were 2419 ng/mL and were maintained to around month 18, reflecting the mean dose of ~20 mg/kg/day (Figure 1). Following dose titration, SF levels began to decrease with an overall median decrease in SF by month 54 of −947 ng/mL. At the time of analysis 137 patients (81.5%) continue to receive deferasirox. Of 31 discontinuations, 13 (7.7%) were due to AEs (drug-related AEs leading to discontinuation included glycosuria [n=3] and proteinuria [n=2]), eight (4.8%) to unsatisfactory therapeutic effect, five (3.0%) to consent withdrawal and four (2.4%) to other reasons. One death (septicemia in a splenectomized patient) occurred, considered by the Program Safety Board unrelated to treatment. Over the study period, the most common drug-related (investigator-assessed) AEs were abdominal pain and vomiting (n=12, 7.1% for both), nausea (n=10, 6.0%) and rash (n=9, 5.4%). The annual frequency of drug-related AEs decreased from year to year. In total, 13 patients (7.7%) had an increase in serum creatinine >33% above baseline and the upper limit of normal (ULN) on two consecutive visits; however, there were no progressive increases. Six patients (3.6%) with a normal baseline alanine aminotransferase (ALT), and five (3.0%) with a baseline ALT >ULN had an ALT increase >10×ULN on at least one visit. Growth, as assessed by height, proceeded normally in this population. Conclusions: Over a median period of 4.7 years, deferasirox treatment provided a dose-dependent overall reduction in iron burden in transfusion-dependent children with β-thalassemia, as measured by SF levels. Deferasirox was generally well tolerated with the frequency of investigator-reported AEs decreasing over long-term treatment. Figure 1. Mean dose and median change in SF during deferasirox treatment in pediatric β-thalassemia patients Figure 1. Mean dose and median change in SF during deferasirox treatment in pediatric β-thalassemia patients

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Transfusion History, Iron Chelation Practices and Status of Iron Overload across Various Transfusion-Dependent Anemias: Data from the Large- Scale, Prospective, 1-Year EPIC Trial

Blood ◽

10.1182/blood.v112.11.3880.3880 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3880-3880

Author(s):

Maria Domenica Cappellini ◽

Norbert Gattermann ◽

Vip Viprakasit ◽

Jong Wook Lee ◽

John B Porter ◽

...

Keyword(s):

Iron Overload ◽

Large Scale ◽

Chelation Therapy ◽

Iron Concentration ◽

Iron Chelation ◽

Dry Weight ◽

Thalassemia Major ◽

Liver Iron ◽

Baseline Characteristics ◽

Transfusion History

Abstract Background: The prospective, 1-yr multicenter EPIC trial evaluated the efficacy and safety of once-daily oral deferasirox (Exjade®) in more than 1700 patients (pts) with transfusion-dependent anemias. Data were collected from each patient at enrollment, providing an insight into transfusion history, body iron burden, and the nature and success of previous chelation therapy in a large group of pts with iron overload previously treated with chelation therapy. Methods: Enrolled pts were aged ≥2 yrs, had transfusion-dependent anemia and serum ferritin (SF) levels of ≥1000 ng/mL, or <1000 ng/mL with a history of multiple transfusions (>20 transfusions or >100 mL/kg of RBCs) and MRI-assessed liver iron concentration (LIC) >2 mg Fe/g dry weight (dw). Baseline assessments included transfusion history, previous chelation therapy, SF levels and LIC (if carried out) in the previous yr. Results: 1744 pts (901 M, 843 F) were enrolled. Underlying anemias were: thalassemia major (TM; n=937), thalassemia intermedia (TI; n=84), myelodysplastic syndromes (MDS; n=341), aplastic anemia (AA; n=116), sickle cell disease (SCD; n=80), rare anemias (red cell aplasia and anemias mostly hemolytic in nature; n=43), Diamond-Blackfan anemia (DBA; n=14), and various other conditions associated with anemias requiring transfusion (n=129). Baseline characteristics for key underlying anemias are presented in Table 1. Median SF levels were >2500 ng/mL and mean LIC in the previous yr was >7 mg Fe/g dw in all groups (except DBA for SF levels). MDS pts had received the most transfusions in the previous yr, although they had also spent a smaller proportion of their lifetime, and less total time, receiving transfusions than any other cohort. Together with AA pts, the MDS cohort also contained the highest proportion of pts who were chelation-naïve (68% and 48%). SCD pts were the least-transfused group in terms of amount of blood given, but had been receiving transfusions for more than 13 yrs. As expected, TM pts had spent the greatest proportion of their lifetime on transfusions and received the greatest volume of blood per kg in the previous yr. The group labeled by investigators as TI were relatively heavily transfused for this patient population. Table 1. Baseline characteristics for key underlying anemias All (n=1744) TM (n=937) TI (n=84) MDS (n=341) AA (n=116) SCD (n=80) Rare (n=43) DBA (n=14) *Mean ± SD; **Median Age, yrs* 30.6±23.3 18.4±10.8 19.2±14.4 67.9±11.4 33.3±17.1 23.9±13.2 39.5±22.7 17.3±13.2 Transfusions in last yr* 17.8±12.5 17.5±8.8 13.5±7.1 24.3±17.7 12.5±13.0 10.7±8.2 21.0±18.7 19.0±18.7 Total transfused in last yr, mL/kg* 159±136 190±139 155±87 116±123 116±179 84±57 153±142 185±148 Total yrs on transfusions* 12.3±10.4 16.8±10.4 10.2±7.8 3.6±4.6 6.1±5.7 13.0±9.6 10.9±11.8 13.3±10.0 % of lifetime on transfusions* 62.9±39.4 89.8±15.2 61.2±28.8 5.7±8.4 27.1±29.3 59.5±30.1 44.3±41.5 87.5±23.2 LIC in last yr, mg Fe/g dw* 10.7±9.0 9.5±7.8 9.7±5.5 14.4±8.5 12.0±4.3 11.8±8.4 – 8.8±4.2 SF, ng/mL** 3135 3157 3493 2730 3254 3163 3161 2289 Prior chelation, % DFO 58.6 66.7 78.6 40.2 26.7 62.5 55.8 71.4 Deferiprone 1.6 1.3 – 4.1 – 1.3 2.3 – DFO/deferiprone 16.7 25.0 4.8 7.0 5.2 12.5 11.6 14.3 Other 0.3 0.4 – 0.3 – – – – None 23.0 7.0 16.7 48.4 68.1 23.8 30.2 14.3 Conclusions: Data from this study population show that, although most pts with thalassemia, SCD, DBA and rare anemias had received previous chelation therapy, LIC and SF levels were above levels associated with significant negative outcomes (>7 mg Fe/g dw and >2500 ng/mL, respectively), which suggests that previous chelation practices were sub-optimal. Many pts with MDS and AA were chelation-naïve despite being heavily iron overloaded, highlighting that the risks of iron overload are still underestimated. These data highlight the need to carefully monitor iron levels in pts at risk of iron overload and initiate chelation therapy to avoid serious clinical sequelae.

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Efficacy and Safety of Deferasirox (Exjade®) with up to 4.5 Years of Treatment in Patients with Thalassemia Major: A Pooled Analysis

Blood ◽

10.1182/blood.v112.11.5411.5411 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5411-5411 ◽

Cited By ~ 3

Author(s):

Maria Domenica Cappellini ◽

Renzo Galanello ◽

Antonio Piga ◽

Alan Cohen ◽

Antonis Kattamis ◽

...

Keyword(s):

Serum Ferritin ◽

Iron Concentration ◽

Efficacy And Safety ◽

Iron Intake ◽

Liver Iron ◽

Common Drug ◽

Median Serum ◽

Daily Dose ◽

Annual Frequency

Abstract Background: Assessing the long-term efficacy and safety of iron chelation therapy is important given that patients with β-thalassemia require lifelong treatment. The efficacy and safety of deferasirox (Exjade®), a once-daily, oral iron chelator was established in patients with β-thalassemia in four 1-year core trials. Initial doses were assigned by baseline liver iron concentration and a clear dose response was observed. Subsequent data highlighted that a number of factors need to be considered when adjusting deferasirox dose, including iron burden and transfusional iron intake. Dose adjustments were permitted in the extension phases to the 1-year core trials, to ensure that optimal dosing was achievable. This analysis evaluates efficacy and safety during up to 4.5 years of deferasirox treatment in adult and pediatric patients with β-thalassemia. Methods: Following 1 year’s treatment with deferasirox in the four core studies, iron overloaded patients with β-thalassemia were enrolled in 4-year extension trials (105E–108E) evaluating the long-term efficacy and safety of deferasirox. Deferasirox doses in the extension trials were initially based on end-of-core liver iron concentration (LIC) and were subsequently adjusted according to serum ferritin (SF) levels. Efficacy was monitored by monthly SF levels; safety was assessed by the incidence and type of adverse events (AEs) and changes in laboratory parameters. Results: In total, 472 patients with β-thalassemia are included in this analysis. Patients received deferasirox for a median period of 55 months (4.6 years) at an overall mean ± SD daily dose of 22.1 ± 6.4 mg/kg. Mean iron intake over the entire treatment period was 0.4 ± 0.1 mg/kg/day. Median SF was 2319 ng/mL at baseline; change from baseline in SF was 158 ng/mL at 12 months, during which time the mean daily dose was ~19.5 mg/kg/day. Following 1-year’s treatment, dose adjustments were permitted and by 54 months (4.5 years) median SF had decreased significantly from baseline by 931 ng/mL (P<0.0001; Wilcoxon signed rank test). Mean deferasirox dose had increased to 25.2 mg/kg/day by month 54 (Figure 1). Figure 1. Mean dose and median serum ferritin during deferasirox treatment Figure 1. Mean dose and median serum ferritin during deferasirox treatment Over the treatment period, 159 patients discontinued because of: consent withdrawal due mainly to the commercial availability of deferasirox (n=52, 11.0%), AEs (n=50, 10.6%), unsatisfactory therapeutic effect (n=39, 8.3%), and other reasons (n=13, 2.8%). Five deaths occurred (one in the core and four in the extension phases), all of which were considered by the Program Safety Board as unrelated to deferasirox. Overall, the most common drug-related (investigator-assessed) AEs were abdominal pain (n=62, 13.1%), nausea (n=55, 11.7%), diarrhea (n=40, 8.5%), vomiting (n=32, 6.8%) and rash (n=23, 4.9%); the annual frequency of these AEs decreased from year to year, ranging from 0–2.3% in years 2 to 5. The types of drug-related AEs in the extension trials were similar in nature to those in the core trials. The most common drug-related AEs that led to discontinuation were increased transaminases (n=7), glycosuria and proteinuria (n=3 for both). Thirty-four patients (7.2%) had an increase in serum creatinine >33% above baseline and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases or increase in the annual frequency from year to year. Twenty-nine (6.1%) patients had an increase in alanine aminotransferase >10 × ULN on at least one visit; baseline levels were already >ULN in 18 patients. Conclusions: Over 4.5 years’ treatment, deferasirox provided a dose-dependent reduction in SF in patients with β-thalassemia. Deferasirox was generally well tolerated with the frequency of investigator-reported AEs decreasing over long-term treatment. There were no changes in liver or renal function that differed significantly from the 1-year core trials and there was no evidence of progressive liver/renal dysfunction.

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Iron Chelation in Regularly Transfused Patients with Aplastic Anemia: Efficacy and Safety Results from the Large Deferasirox EPIC Trial

Blood ◽

10.1182/blood.v112.11.439.439 ◽

2008 ◽

Vol 112 (11) ◽

pp. 439-439 ◽

Cited By ~ 1

Author(s):

Jong Wook Lee ◽

Sung-Soo Yoon ◽

Zhi Xiang Shen ◽

Hui-Chi Hsu ◽

Arnold Ganser ◽

...

Keyword(s):

Abdominal Pain ◽

Aplastic Anemia ◽

Iron Reduction ◽

Chelation Therapy ◽

Iron Concentration ◽

Iron Chelation ◽

Efficacy And Safety ◽

Iron Intake ◽

Liver Iron ◽

Transfusion Requirements

Abstract Background: Patients with aplastic anemia (AA) can be effectively treated with bone marrow transplantation or immunosuppressive/immunomodulatory therapy, but many will require repeated blood transfusions to manage symptoms of severe anemia and are subsequently at risk of accumulating excessive body iron. Reduction in iron burden across a range of transfusion-dependent anemias, including AA, has been previously demonstrated with deferasirox (Exjade®). More recently, the EPIC trial enrolled the largest cohort of patients with AA undergoing iron chelation to date. The efficacy and safety of deferasirox in these patients are presented. Methods: Enrolled patients had transfusion-dependent AA and serum ferritin (SF) levels of □1000 ng/mL, or <1000 ng/mL with a history of multiple transfusions (>20 transfusions or 100 mL/kg of red blood cells) and an R2 MRI-confirmed liver iron concentration (LIC) >2 mg Fe/g dry weight. Deferasirox was administered at an initial dose of 10–30 mg/kg/day depending on transfusion requirements, with dose adjustments in steps of 5–10 mg/kg/day (in the range 0–40 mg/kg/day) based on assessment of SF trends and safety markers indicative of iron toxicity. SF was assessed every 4 weeks and the primary efficacy endpoint was the change at week 52 from baseline. Safety assessments included adverse event (AE) monitoring and assessment of laboratory parameters. Results: In total, 116 AA patients (67 males, 49 females; mean age 33.3 years) were enrolled. Median baseline SF was 3254.0 ng/mL; patients received a mean of 115.8 mL/kg of blood in the year prior to enrollment. Approximately two-thirds of patients (68.1%) had received no prior chelation therapy. Of those who had, patients received deferoxamine (DFO; n=31, 26.7%) or combination DFO/deferiprone (n=6, 5.2%). After 12 months, median SF decreased significantly by 964.0 ng/mL from baseline median of 3254.0 ng/mL (P=0.0003). This occurred at an average actual deferasirox dose of 17.6±4.8 mg/kg/day. The median change in SF from baseline was –970.0 ng/mL (P<0.0001; 3263.0 ng/mL [baseline]; 0.20 mg/kg/day [mean iron intake]) in patients receiving a mean actual deferasirox dose <20 mg/kg/day (n=75) and −883.8 ng/mL (P=0.27; 3238.0 ng/mL [baseline]; 0.29 mg/kg/day [mean iron intake]) in those receiving 20–<30 mg/kg/day (n=40). Overall, 88 patients (76%) completed the study; reasons for discontinuation included AEs (n=13, 11%), consent withdrawal (n=6, 5%), lost to follow-up (n=1, 1%) and various other reasons (n=3, 3%). In addition, five patients (4%) died during the study (one death related to pneumonia, three due to sepsis and one as a result of hepatic adenoma rupture). No death was suspected by investigators to be treatment related. The most common drug-related AEs (investigator-assessed) were: nausea (n=26, 22%), diarrhea (n=18, 16%), rash (n=13, 11%), vomiting (n=10, 9%), dyspepsia (n=9, 8%), abdominal pain (n=7, 6%), upper abdominal pain (n=7, 6%), and anorexia (n=7, 6%). Most AEs were mild or moderate in severity (>95%). 29 patients (25.0%) had an increase in serum creatinine >33% above baseline and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases. One patient (0.9%) had an increase in alanine aminotransferase (ALT) that exceeded >10xULN on two consecutive visits; ALT levels were elevated in this patient at baseline. Conclusions: Over a 1-year treatment period, deferasirox significantly reduced iron burden in transfusion-dependent, iron overloaded patients with AA. Despite the high iron burden, most patients had received no prior chelation therapy, indicating a clear need for iron chelation in this patient population. Overall, deferasirox was generally well tolerated in these AA patients with the majority of AEs being mild to moderate.

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Safe and Efficient Chelation by Deferasirox In Thalassemia Major Patients with Low Liver and Cardiac Iron Concentrations

Blood ◽

10.1182/blood.v116.21.5168.5168 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5168-5168

Author(s):

Regine Grosse ◽

Gritta Janka ◽

Andrea Jarisch ◽

Peter Nielsen ◽

Jin Yamamura ◽

...

Keyword(s):

Side Effects ◽

Conflicts Of Interest ◽

Iron Concentration ◽

Iron Chelation ◽

Thalassemia Major ◽

Transfusion Rate ◽

Liver Iron Concentration ◽

Measurement Interval ◽

Liver Iron ◽

Rbc Transfusion

Abstract Abstract 5168 Chelation treatment of iron overload from chronic blood (RBC) transfusion is still a challenge to both, patients and medical caretakers. Different treatment regimes have been recommended so far, especially for chronically transfused patients with low or even normal liver iron concentration. We report the results from 16 regularly transfused patients with thalassemia major (TM) who were on iron chelation treatment under normal to mild liver iron concentration (LIC). All patients received deferoxamine (DFO) treatment before they changed to deferasirox (DSX) treatment. 16 TM patients (mean age 13.6 y) were treated with DSX (median dose 18 mg/kg/d, range: 7 – 33 mg/kg/d) for 6 to 71 months. Liver iron measurements by biomagnetic susceptometry (BLS) and/or MRI-R2 as well as cardiac MRI-R2* were performed in intervals of 6 to 12 months. The median LIC was 782 μ g/g-liver wet weight (range: 460 μ g – 1122 μ g). Median RBC transfusion rate was 8500 ml/y, equivalent to about 2 erythrocyte concentrates per 3 weeks or a daily iron influx of 16.2 mg/d. For each measurement interval, the ratio of daily iron influx and DSX dose rate was calculated. This represents the equilibrium molar efficacy for iron balance. In all 16 TM patients no severe side effects were observed and creatinine was in the normal range of < 0.9 mg/d throughout the treatment with DSX. From baseline DFO treatment interval to the endpoint of DSX treatment, liver iron decreased by 124 – 4689 μ g/g-liver (conversion factor of 6 for mg/g-dry-wgt), while serum ferritin decreased by -596 to 8283 μ g/l. For all measurement intervals, molar chelation efficacies between 18 % and 56 % were calculated at equilibrium with a median efficacy of 31 % (interquartile range = 16 %). This agrees with molar efficacies of DSX reported earlier, but for relatively higher LIC and chelation doses (Blood 2005; 106(11):#2690 and Blood 2007; 110(11):#2776). The cardiac R2* (median R2* = 38 s-1) was either below the normal threshold of 50 s-1 (T2* > 20 ms) or decreased by about 24 %/y under DSX treatment. In these few patients at low LIC, this was even higher than recently reported. Conclusion: Even in patients with normal to mild LIC iron chelation treatment with DSX is safe, does not result in increased creatinine levels or severe side effects and is as efficient as in patients with higher LIC. Disclosures: No relevant conflicts of interest to declare.

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Long Term Efficacy, Safety and Tolerability (>24 Months) of Twice Daily Dosing of Deferasirox in Transfusion Dependent Thalassemias Who Were Unresponsive to Standard Once Daily Dose

Blood ◽

10.1182/blood.v126.23.958.958 ◽

2015 ◽

Vol 126 (23) ◽

pp. 958-958

Author(s):

Bunchoo Pongtanakul ◽

Vip Viprakasit

Keyword(s):

Iron Overload ◽

Iron Concentration ◽

Iron Chelation ◽

Once Daily ◽

Term Efficacy ◽

Before And After ◽

Baseline Levels ◽

Median Change

Background: Clinical efficacy, safety and tolerability of deferasirox (DFX); a once daily oral iron chelator in transfusion dependent thalassemias (TDT) with iron overload can be achieved by appropriate dosage adjustment based on iron burden and ongoing transfusion iron overload. However, even with recommended DFX dosage, at least 40% of our Thai TDT patients did not appropriately respond to DFX. Patients with unresponsiveness to DFX (UR) was defined as (1) having a rising serum ferritin (SF) trend or (2) having a reduction of SF < 30% of baseline levels (BL) at least 3 consecutive mths, with more than two SF measurements >1500 ng/mL; and (3) receiving once daily DFX at an average dosage > 30 mg/kg/day for at least 6 mths. Previously, twice daily dosing (TWD) of DFX was shown to be effective in patients with UR (Pongtanakul B, et al. Blood Cells Mol Dis. 2013) but long term efficacy, safety and tolerability of TWD of DFX is still lacking. Methods: Patients with UR who received TWD of DFX with the same total dose per day > 24 mths were included. CBC, renal function, urine analysis were performed every 3 wks to monitor possible side effect. SF and liver function test were checked every 6 wks. Tolerability and compliance to DFX were evaluated by direct history taking and drug account prescribed. Responsiveness to TWD of DFX (RP) was defined as the patients who showed a decrease of SF or reduction of liver iron concentration (LIC) by MRI > 30% of the BL at 6 or 12 mths. Results: Twenty four TDT patients received TWD of DFX; 4 patients were excluded due to poor compliance and a short follow up period and 4 patients did not meet RP criteria. Sixteen patients were enrolled; 9 male (56%) with a mean (± SD) age of 9.08 ± 3.84 yrs (range 2.1-24.2 yrs). Clinical diagnoses include; Hb E/β thalassemia. (n=12), β thalassemia major (n=3) and Hb Barts hydrops (n=1). Mean follow up time before switching dose were 17.3 ± 7.3 mths. Average SF at BL before DFX and before TWD were 3,039 ± 1,713.7.02 and 3,500 ± 1,403.2 ng/mL, with median % change of SF was +27.58 % (range; -13.4 to +104%). Mean actual DFX dose during 6 mths before switching was 36.3 ± 2.2 mg/kg/day. None had symptoms of gastrointestinal irritation. After TWD, 13 (81.25%) and 16 patients (100%) showed a significant decrease of SF (> 30% of the baseline levels) at 6 and 12 months. Mean SF and median % change of SF at 6 and 12 months after switching were 2,527.56 ± 1,191.80 ng/mL; -29.24 % and 1,695.83 ± 859.16 ng/mL; -53.14%, with statistical significance compared to BL and before switching (p <0.05). Mean transfusion iron load before and after switching were not different (range 0.2-0.4 mg/kg/day). One patient had a SF reduction < 30%, but LIC was significant reduction at 12 months. Nine out of 16 patients were evaluated for LIC; average LIC at BL and at the end of study were reduced from 6.7 to 3.2 mg/g dry wt. None had cardiac T2* < 20 msec. All patients except one tolerated well with DFX at before and after switching (>24 months) with minor adverse events. One patient had severe transaminitis (ALT > 3 times of ULN) but after investigation, this was thought to be result from acute viral hepatitis. This patient could be successfully restarted DFX at the same TWD. Five patients could decrease DFX dosage to < 20 mg/kg/day and switched back to daily dosing (mean dosage was 17.04 mg/kg/day). However, 4 patients, after decreased DFX dosage and switched back to daily dosing; their SF increased and required to increase DFX dosage with TWD to maintain SF. Seven patients continued to receive TWD of DFX with mean dosage was 36.4 mg/kg/day. Mean follow up time after TWD of DFX was 44.1 + 9.8 mths (range 24 - 72 mths). Conclusion: Herein, we show that TWD of DFX effectively reduced iron burden in TDT with iron overload. Safety and tolerability of this dosing are not different from once daily dosing. Most patients could decrease DFX dosage and switched back to once daily dosing when iron burden decreased. However, 25% (4/16) of these patients still required twice daily dosing with higher dosage to maintain optimal body iron levels. Interestingly, 16% (4/24) of our patients who received TWD could not achieve effective iron chelation. This group of patients may represent those who have different pharmacogenetic background that affect directly to efficacy of DFX causing a resistant to iron chelation therapy. This population confirms for improving iron chelation measures by means of a newer iron chelation agent or a combination of DFX with other iron chelation. Disclosures Off Label Use: Twice daily dosing instead of standard daily dosing.

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Deferasirox Decreases Liver Iron Concentration in Iron-Overloaded Patients with Myelodysplastic Syndromes, Aplastic Anemia and Other Rare Anemias

Acta Haematologica ◽

10.1159/000381893 ◽

2015 ◽

Vol 134 (4) ◽

pp. 233-242 ◽

Cited By ~ 9

Author(s):

Yutaka Kohgo ◽

Akio Urabe ◽

Yurdanur Kilinç ◽

Leyla Agaoglu ◽

Krzysztof Warzocha ◽

...

Keyword(s):

Aplastic Anemia ◽

Myelodysplastic Syndromes ◽

Iron Concentration ◽

Dry Weight ◽

Japanese Patients ◽

Efficacy And Safety ◽

Liver Iron Concentration ◽

Open Label ◽

Liver Iron ◽

Therapeutic Goals

Iron overload in transfusion-dependent patients with rare anemias can be managed with chelation therapy. This study evaluated deferasirox efficacy and safety in patients with myelodysplastic syndromes (MDS), aplastic anemia (AA) or other rare anemias. A 1-year, open-label, multicenter, single-arm, phase II trial was performed with deferasirox (10-40 mg/kg/day, based on transfusion frequency and therapeutic goals), including an optional 1-year extension. The primary end point was a change in liver iron concentration (LIC) after 1 year. Secondary end points included changes in efficacy and safety parameters (including ophthalmologic assessments) overall as well as in a Japanese subpopulation. Overall, 102 patients (42 with MDS, 29 with AA and 31 with other rare anemias) were enrolled; 57 continued into the extension. Mean absolute change in LIC was -10.9 mg Fe/g dry weight (d.w.) after 1 year (baseline: 24.5 mg Fe/g d.w.) and -13.5 mg Fe/g d.w. after 2 years. The most common drug-related adverse event was increased serum creatinine (23.5%), predominantly in MDS patients. Four patients had suspected drug-related ophthalmologic abnormalities. Outcomes in Japanese patients were generally consistent with the overall population. Results confirm deferasirox efficacy in patients with rare anemias, including a Japanese subpopulation. The safety profile was consistent with previous studies and ophthalmologic parameters generally agreed with baseline values (EUDRACT 2006-003337-32).

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