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

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5411-5411 ◽  
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.

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

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 884-893 ◽  
Author(s):  
M. Domenica Cappellini ◽  
Mohamed Bejaoui ◽  
Leyla Agaoglu ◽  
Duran Canatan ◽  
Marcello Capra ◽  
...  
Keyword(s):  
Adverse Events ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Dry Weight ◽  
Thalassemia Major ◽  
Efficacy And Safety ◽  
Liver Iron ◽  
Median Serum

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.

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

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 439-439 ◽  
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 &lt;1000 ng/mL with a history of multiple transfusions (&gt;20 transfusions or 100 mL/kg of red blood cells) and an R2 MRI-confirmed liver iron concentration (LIC) &gt;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&lt;0.0001; 3263.0 ng/mL [baseline]; 0.20 mg/kg/day [mean iron intake]) in patients receiving a mean actual deferasirox dose &lt;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–&lt;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 (&gt;95%). 29 patients (25.0%) had an increase in serum creatinine &gt;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 &gt;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.

Insights into Relationships Between Serum Ferritin and Liver Iron Concentration Trends during 12 Months of Iron Chelation Therapy with Deferasirox – a Post-Hoc Analysis from the Epic Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 52-52 ◽  
Author(s):  
John B Porter ◽  
Mohsen Elalfy ◽  
Ali T Taher ◽  
Lee Lee Chan ◽  
Szu-Hee Lee ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Serum Ferritin ◽  
Research Funding ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Iron Intake ◽  
Advisory Committees ◽  
Liver Iron ◽  
Baseline Serum ◽  
Post Hoc

Abstract Background Serum ferritin is regularly used to assess response to chelation therapy and correlates significantly with liver iron concentration (LIC) particularly when LIC is <7 mg Fe/g dry weight (dw) and serum ferritin is <4000 ng/mL. The absence of a serum ferritin decrease in the first months of a new chelation regime may be interpreted as a lack of response with respect to decreasing body iron load. However, sequential LIC determination (where available) has indicated that many of these patients do indeed have a decrease in LIC. This clinical experience requires greater understanding, particularly the nature of the LIC and serum ferritin relationship at baseline serum ferritin values ≥4000 ng/mL. The aim of this post-hoc analysis of the EPIC study was to gain insight into the relationship between serum ferritin and LIC in response to deferasirox over 1 year, in a large patient cohort, so that serum ferritin trends can be more clearly interpreted and evidence-based practical guidance be given for patients with transfusion-dependent thalassemia (TDT). Methods TDT patients were recruited from 25 sites, received 1-year of deferasirox treatment and had serum ferritin and R2 magnetic resonance imaging (R2-MRI)-assessed LIC measurements at baseline and 1 year. Summary statistics are provided for serum ferritin and LIC responders (decrease, any change from baseline <0) and nonresponders (increase or no change, any change from baseline ≥0), and for baseline serum ferritin categories (≥4000 vs <4000 ng/mL). Results Of the 374 patients analyzed in the EPIC liver MRI substudy, 317 had TDT, of which 72.7% (n=226) had a serum ferritin response and 27.3% (n=85) had no response. Importantly, after 1 year LIC decreased in approximately half of serum ferritin nonresponders (51.8%; n=44; Table) and in 79.6% of serum ferritin responders (n=180). Median (min, Q1, Q3, max) change in LIC (mg Fe/g dw) was –5.4 (–38.5, –11.7, –0.9, 15.4) in serum ferritin responders and –0.2 (–18.4, –2.6, 2.7, 19.6) in nonresponders. Median (range) transfusional iron intake (mg/kg/day) was similar in serum ferritin responders (0.30 [0.01–1.49]) and nonresponders (0.37 [0.02–1.00]). Median deferasirox dose (mg/kg/day) was higher in serum ferritin responders than nonresponders (28.1 [9.8–40.4] vs 23.7 [9.7–37.9]). Evaluation of responses by baseline serum ferritin showed that a greater proportion of serum ferritin responders with baseline serum ferritin <4000 ng/mL also had decreased LIC (88.7% [n=102]; Table), compared with serum ferritin responders with baseline serum ferritin ≥4000 ng/mL (70.3% [n=78]). However, serum ferritin baseline category had no effect on the proportion of patients who decreased LIC despite having no serum ferritin response (52.6% [n=30], <4000 ng/mL; 50.0% [n=14], ≥4000 ng/mL; Table). There was little change in median LIC in serum ferritin nonresponders after 1 year regardless of baseline serum ferritin value (–0.3 [–13.5–18.7] for <4000 ng/mL and 0.2 [–18.4–19.6] for ≥4000 ng/mL). Assessment by change in serum ferritin and LIC quadrants indicated that patients without serum ferritin or LIC response had the lowest baseline median (range) serum ferritin and LIC (2155 [480–9725] ng/mL; 11.9 [1.8–37.5] mg Fe/g dw; n=41), and received a lower median deferasirox dose (23.7 [9.7–36.0] mg/kg/day). Overall, median LIC decrease (mg Fe/g dw) was smaller in patients with baseline serum ferritin <4000 ng/mL (n=172) than in those with serum ferritin ≥4000 ng/mL (–2.8 [–38.5–18.7] vs –4.9 [–31.1–19.6]; n=139). Median iron intake was similar between groups. Discussion and conclusions A decrease in LIC was seen in ~80% of serum ferritin responders after 1 year of deferasirox; a greater proportion of serum ferritin responders (88%) decreased LIC when baseline serum ferritin was <4000 ng/mL. Importantly, among patients with no serum ferritin response up to half may be responding with respect to iron balance, indicating that a lack of serum ferritin response should be interpreted with caution. However, since a decrease in serum ferritin predicts a decrease in LIC in 80% of patients, MRI measurement (where available) should be prioritized for patients with serum ferritin increase/no change. Overall, serum ferritin response can help predict LIC response, but in some patients treated with deferasirox, serum ferritin may not accurately reflect removal of iron from the body. Figure 1 Figure 1. Disclosures Porter: Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy; Cerus: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees. Taher:Novartis: Honoraria, Research Funding. Sutcharitchan:Novartis: Research Funding. Aydinok:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Chakravarty:Novartis: Employment. El-Ali:Novartis: Employment.

Efficacy and Safety of Once-Daily, Oral Iron Chelator Deferasirox (Exjade®) in a Large Group of Regularly Transfused Patients with β-Thalassemia Major

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3878-3878 ◽  
Author(s):  
Maria Domenica Cappellini ◽  
Mohsen Saleh Elalfy ◽  
Antonis Kattamis ◽  
John F Seymour ◽  
Chan Lee Lee ◽  
...  
Keyword(s):  
Iron Concentration ◽  
Chelating Agent ◽  
Thalassemia Major ◽  
P Value ◽  
Efficacy And Safety ◽  
Iron Intake ◽  
Liver Iron ◽  
Once Daily ◽  
Transfusion Requirements ◽  
Median Change

Abstract Background: The 1-year, prospective, multicenter EPIC trial, the largest ever conducted for an iron-chelating agent, evaluated the efficacy and safety of the once-daily, oral chelator deferasirox (Exjade®) in patients (pts) with transfusion-dependent anemias. 54% of 1744 pts had β-thalassemia major, providing one of the largest data sets assessing the use of deferasirox in this group. Data from this subgroup are presented. Methods: Pts (≥2 years old) with transfusional iron overload due to β-thalassemia and serum ferritin (SF) levels of ≥1000 ng/mL or <1000 ng/mL but with a history of multiple transfusions (>20 transfusions or 100 mL/kg of blood) and R2 MRI-confirmed liver iron concentration >2 mg Fe/g dry weight, received an initial deferasirox dose of 10–30 mg/kg/day dependent on transfusion requirements. Protocol-specified dose adjustments in steps of 5–10 mg/kg/day (range 0–40 mg/kg/day) were done every 3 months based on SF trends and safety markers. The change at week 52 from baseline (BL) was the primary efficacy endpoint. Results: 937 pts with β-thalassemia major, 450 males and 487 females (mean age 18.4±10.8 years), were enrolled. Median BL SF was 3157 ng/mL (range 462–22320). In the year prior to enrollment, pts received a mean of 189.8 mL/kg of blood (range 0–1768). Most pts (n=625; 66.7%) had received deferoxamine (DFO); 234 (25.0%) DFO/deferiprone combination, 12 (1.3%) deferiprone alone and four (0.4%) other therapy; 66 (7.0%) were chelation naive. 798 pts (85%) started on ≤20 mg/kg/day and 139 (15%) on >20 mg/kg/day. 51% required a dose increase at a median of 24 weeks after treatment initiation (range 2–53). After 1 year, median SF significantly decreased from BL by 129 ng/mL (P=0.0007) at an average actual dose of 24.2±5.6 mg/kg/day. Pts receiving an average actual dose of ≥30 mg/kg/day achieved a significant reduction in SF at 1 year. Pts receiving an average actual dose of <20 or ≥20–<30 mg/kg/day maintained their iron balance. SF change by mean actual dose received is shown in Table 1. The magnitude of reduction in SF was reflective of dose adjustments throughout the study. Table 1. Median change from BL in SF (ng/mL) by average actual dose received BL End of study Average actual dose categories Mean iron intake, mg/kg/day n Median SF n Median change from BL in SF P -value versus BL <20 mg/kg/day 0.38 193 2318 187 −14 0.67 ≥20–<30 mg/kg/day 0.46 614 3108 611 −45 0.56 ≥30 mg/kg/day 0.35 130 5154 130 −962 <0.0001 All pts 0.43 937 3157 928 −129 0.0007 Only 9.5% of pts (n=89) discontinued therapy. Reasons for withdrawal were AEs (n=31, 3.3%), consent withdrawal (n=24, 2.6%), unsatisfactory therapeutic effect (n=12, 1.3%), lost to follow-up (n=5, 0.5%), death (n=4, 0.4%, three due to cardiac failure and one to septicemia following surgery, none treatment related by investigators’ assessment) and other (n=13, 1.4%). The most common investigator-assessed drug-related AEs were rash (n=115, 12.3%), diarrhea (n=76, 8.1%) and abdominal pain (n=50, 5.3%). The majority of AEs were mild-to-moderate (>95%). Thirty-seven pts (3.9%) had serum creatinine >33% above BL and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases. Five (0.5%) pts had an increase in alanine aminotransferase >10×ULN on two consecutive visits; levels were already elevated in four pts. Conclusions: These data confirm that in heavily iron-loaded pts with β-thalassemia major, higher deferasirox doses are needed to achieve significant reductions in SF, while lower doses are able to maintain iron balance. The starting dose guided by the rate of iron intake from blood transfusions and current iron burden should be titrated individually and promptly (at 3 months) according to SF trends and safety markers. Deferasirox treatment in this subgroup was generally well tolerated (including doses ≥30 mg/kg/day) with a low discontinuation rate.

Impact of Dose Adjustments on Serum Ferritin (SF) Levels during Long-Term Treatment with Once-Daily, Oral Deferasirox (Exjade®, ICL670).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2778-2778 ◽  
Author(s):  
John B. Porter ◽  
Alan R. Cohen ◽  
John M. Ford ◽  
Maria Domenica Cappellini
Keyword(s):  
Serum Ferritin ◽  
Iron Concentration ◽  
Iron Intake ◽  
Long Term Effects ◽  
Subsequent Dose ◽  
Body Iron ◽  
Number Of Patients ◽  
Long Term Treatment ◽  
The Impact

Abstract Background: In deferasirox 1-yr core trials, doses were initially assigned according to baseline liver iron concentration. However, these trials demonstrated that transfusional iron intake has a profound impact on the outcome of chelation therapy and should therefore be considered when assigning deferasirox dose. A large number of patients (pts) were initially assigned 5 and 10 mg/kg/d doses, which were insufficient to balance iron intake from ongoing transfusions. Generally, deferasirox 20/30 mg/kg/d effectively maintained/reduced body iron. This analysis from the 4-yr extension trials evaluates the impact on serum ferritin (SF) of subsequent dose increases in pts who initially received 5/10 mg/kg/d, and the long-term effects of 20 and 30 mg/kg/d doses. Methods: Data for this analysis were pooled from 4 extension trials (106–109E). In the extensions, deferasirox doses were modified based on efficacy and safety markers, including iron burden and transfusional iron intake. SF was measured monthly. Results: In total, 227 pts initially received deferasirox 5 or 10 mg/kg/d, while 182 and 243 received 20 and 30 mg/kg/d, respectively. Underlying diseases included β-thalassemia (n=421), sickle cell disease (n=132), MDS (n=47) and other anemias (n=52). To date, pts have been receiving treatment for a median 3.4 (range: 0–4.5) yrs. Overall, median SF was maintained in the 20 mg/kg/d cohort (Table). In the 30 mg/kg/d cohort, SF levels decreased overall from baseline to month 42 (3734 ng/mL to 2025 ng/mL). However, levels plateaued at around 24 mos in this cohort, reflecting a decrease in mean dose to around 25 mg/kg/d. Median baseline SF in the 5/10 mg/kg/d dose group was 2051 ng/mL, which steadily increased during the first 18 mos of treatment. Subsequent dose increases during the extension phase generally resulted in decreased SF levels, which returned to baseline and below during the remainder of the study. Conclusions: In regularly transfused pts who initially received deferasirox 5/10 mg/kg/d in the core 1-yr clinical trials, SF steadily decreased below baseline once doses were increased to an appropriate level in the extensions. This highlights the importance of ensuring that pts receive the correct deferasirox dose to achieve the goal of therapy, based on iron burden and transfusional iron intake. If a pt is not achieving their therapeutic goal based on SF trends, deferasirox dose should be increased in steps of 5 or 10 mg/kg/d. This analysis confirms that deferasirox 30 mg/kg/d effectively reduces body iron, whereas doses of 20–25 mg/kg/d are generally effective in maintaining iron levels. Median change from baseline in SF (ng/mL) during deferasirox treatment of up to 3.4 years Initial dose, mg/kg/d 5/10 (n=227*) 20 (n=182*) 30 (n=243*) Month Mean dose ± SD† Change in SF (ng/mL) Mean dose ± SD† Change in SF (ng/mL) Mean dose ± SD† Change in SF (ng/mL) *Baseline; †At time point Baseline 2051 2375 3734 1 9.4 ± 1.7 90 19.5 ± 2.6 30 29.2 ± 4.3 −212 6 10.3 ± 3.9 399 18.9 ± 3.5 −15 28.2 ± 5.7 −532 12 13.0 ± 5.4 613 19.0 ± 4.0 −118 26.8 ± 6.6 −716 18 18.5 ± 6.7 831 18.2 ± 7.7 174 23.1 ± 8.6 −676 24 21.7 ± 6.6 635 21.5 ± 6.5 −125 24.5 ± 7.6 −901 30 22.6 ± 7.0 317 22.0 ± 8.5 −205 24.4 ± 8.0 −959 36 21.1 ± 8.7 −211 22.8 ± 7.7 −159 24.3 ± 8.5 −1002 42 21.8 ± 9.3 −65 23.2 ± 8.2 −204 25.8 ± 9.8 −955 EOS 1345 1667 2025

Long-Term Treatment with Deferasirox (Exjade®, ICL670), a Once-Daily Oral Iron Chelator, Is Effective in Patients with Transfusion-Dependent Anemias.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2777-2777 ◽  
Author(s):  
Maria Domenica Cappellini ◽  
Elliott Vichinsky ◽  
Renzo Galanello ◽  
Antonio Piga ◽  
Paul Williamson ◽  
...  
Keyword(s):  
Liver Toxicity ◽  
Iron Concentration ◽  
Safety Data ◽  
Multiple Infections ◽  
Efficacy And Safety ◽  
Drug Induced ◽  
Liver Iron ◽  
The Core ◽  
Long Term Treatment

Abstract Background: The efficacy and safety of deferasirox was established during five 1-year core trials. As many patients will require lifelong chelation therapy, assessing long-term efficacy and safety is important. In the core trials, initial doses were assigned by baseline liver iron concentration (LIC). A clear dose response was observed: 5/10 mg/kg/d doses were generally insufficient to balance iron intake from ongoing transfusions, while 20 and 30 mg/kg/d maintained or reduced iron balance, respectively. This analysis evaluates serum ferritin (SF) levels and cumulative safety data during 4-year extension trials. Methods: In the extensions, dose modifications were based on safety and efficacy parameters. Safety and SF were assessed monthly. Due to methodological differences in study 105, the SF data from this trial are not included in this analysis. Results: 1034 patients with β-thalassemia (n=750), sickle cell disease (n=185), MDS (n=47) and other anemias (n=52) have received deferasirox. 703 patients received deferasirox in the core trials and have been on treatment for a median of 3.4 years; 331 crossed over to deferasirox in the extensions. 210 (20%) patients have discontinued treatment due to: AEs (74), consent withdrawal (64), unsatisfactory therapeutic effect (29) and other (43). Only 17 (1.6%) patients have discontinued in the past 12 months (9 AEs; 1 death; 4 lost to follow-up; 2 withdrew consent; 1 other). 16 patients have died, 6 in the core and 10 in the extensions. 5 patients (4 β-thalassemia, 1 sideroblastic anemia) aged 18-24 years with inadequate chelation and severe iron overload before study entry died with cardiac failure in the extensions. Other deaths were due to other complications/progression of the underlying disease. At month 42, mean (SD) dose in the 5/10, 20 and 30 mg/kg/d dose groups was 21.8 (9.3), 23.2 (8.2) and 25.4 (9.8) mg/kg/d, respectively. Median SF levels (ng/mL) are shown in the Table (n=652, deferasirox cohort only). Drug-related AEs during deferasirox treatment were generally transient, of mild/moderate severity, and showed a reduction in frequency from the core trials. No patient has developed progressive increases in serum creatinine or values >2 x ULN. 2 patients discontinued due to stable creatinine increases of 1.5 x ULN and confounding circumstances (concomitant cyclosporine and multiple infections, respectively). 1 patient discontinued due to recurrent episodes of proteinuria. 12 patients discontinued due to increases in transaminases (4 core study, 8 extension [3 crossover patients]). Drug-induced liver toxicity was likely in 2 patients with early onset and positive rechallenge. Increasing LIC due to under-chelation was the likely explanation in at least some patients. Conclusions: Over 3.5 years’ treatment, deferasirox 20/30 mg/kg/d maintained/reduced SF levels in patients with various transfusion-dependent anemias. There was no increase in frequency of drug-related AEs or changes in markers of liver or renal function that differed significantly from the 1-year core trials. Initial dose, mg/kg/d *Dose adjustments Month 5/10 (n=227) 20 (n=182) 30 (n=243) Baseline 2051 2375 3734 12* 2650 2161 2649 24 2481 2508 2271 36 1439 1844 2071 42 1345 1667 2025

Long Term Erythrocytapheresis Is Associated with Reduced Liver Iron Concentration in Sickle Cell Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4867-4867
Author(s):  
Scott N. Myers ◽  
Ryan Eid ◽  
John Myers ◽  
Salvatore J. Bertolone ◽  
Ashok B. Raj
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Cell Disease ◽  
Liver Iron ◽  
Serial Serum ◽  
Low Levels ◽  
The Impact

Abstract Background: Observational studies and randomized clinical trials have demonstrated that RBC transfusions can alleviate or prevent many complications of sickle cell disease (SCD). Obligatory iron loading is most problematic for those receiving chronic simple transfusions and is managed with chelation therapy to prevent hepatic, cardiac, and endocrinologic complications. Erythrocytapheresis procedures are increasingly used in SCD as they achieve dilution of hemoglobin S without significantly raising the total hematocrit. Some guidelines for the management of iron overload use serum ferritin levels, but non-invasive measurements of liver iron concentration (LIC) using validated and widely available MRI techniques have been described. There is a paucity of data elucidating the impact of long-term erythrocytapheresis (LTE) on LIC. We evaluated LIC with MRI and serial serum ferritin measurements among a population of SCD patients maintained on LTE at a single institution. Methods: Subjects with SCD maintained on the LTE program included those with elevated TCD, history of stroke, recurrent acute chest syndrome, or frequent pain crises unresponsive to hydroxyurea therapy. Serial serum ferritin measurements were followed and chelation with deferasirox was initiated for consistent ferritin level >1000 ng/mL. MRI of liver and cardiac iron was measured on all LTE subjects with non-contrast MRI techniques. A total of n=31 subjects maintained on LTE were enrolled and stratified into two groups: high LIC, ≥5mg/g of dry tissue (n=4, 12.9%) and low LIC, <5mg/g (n=27, 87.1%). Chi-squared and t-test were used to test for differences between the two groups. Logistic regression was used to test what impacted the odds of having a high LIC, while generalized linear mixed-effects modeling was used to test what impacted LIC. Results: None of the subjects had high cardiac iron concentration. Subjects with high LIC were significantly older (17.8 vs. 13.1, p=0.032) and were more likely to be female (100% vs. 44.4%, p=0.038). The duration of LTE was not associated with high and low levels of LIC (8.25 vs. 6.15, p=0.240, Figure 1), levels of LIC (r=0.247, p=0.188, Figure 2), or serum ferritin (r=0.077, p=0.680). The total number of simple of transfusions was not associated with serum ferritin (r=-0.177, p=0.558) or LIC (r=-0.022, p=0.910). Serum ferritin was not significantly associated with LIC (r=0.296, p=0.112, Figure 3). One of the 4 patients with high LIC required chelation with deferasirox for ferritin >1000 ng/mL. Three of the 31 subjects required iron chelation with deferasirox. Conclusions: There was no significant correlation between duration of LTE and LIC. The impact of cumulative simple transfusions on LIC was obviated by maintenance LTE. These findings are consistent with reports that LTE is associated with reduced transfusional iron overload. The lack of significant association between serum ferritin and LIC suggest that validated MRI measurements of LIC may have greater sensitivity for identifying patients with iron overload and guidelines for iron chelation should consider LIC rather than serum ferritin alone. Figure 1. Duration of LTE (years) was not associated with high and low levels of LIC. Figure 1. Duration of LTE (years) was not associated with high and low levels of LIC. Figure 2. Duration of LTE was not associated with levels of LIC. Figure 2. Duration of LTE was not associated with levels of LIC. Figure 3. Serum ferritin was not significantly associated with LIC. Figure 3. Serum ferritin was not significantly associated with LIC. Disclosures No relevant conflicts of interest to declare.

Deferasirox (Exjade®, ICL670) Demonstrates Iron Chelating Efficacy Related to Transfusional Iron Intake in Pediatric Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2692-2692 ◽  
Author(s):  
C. Kattamis ◽  
Y. Kilinc ◽  
S. Fattoum ◽  
A. Ferster ◽  
D. Gallisai ◽  
...  
Keyword(s):  
Serum Ferritin ◽  
Safety Profile ◽  
Pediatric Patients ◽  
Iron Concentration ◽  
Phase Iii ◽  
Average Dose ◽  
Iron Intake ◽  
Open Label ◽  
Liver Iron ◽  
Transfusion Requirements

Abstract Chelation therapy is the conventional treatment for transfusional iron overload, which leads to complications in the heart, liver and endocrine glands. A 1-year, open-label, multicenter, Phase III study compared the investigational, once-daily, oral iron chelator deferasirox (DSX) with deferoxamine (DFO) in adult and pediatric β-thalassemia patients aged ≥ 2 years. Patients with liver iron concentration (LIC) of 2–3, &gt;3–7, &gt;7–14 and &gt;14 mg Fe/g dw were randomized to receive daily DSX 5, 10, 20 and 30 mg/kg or DFO 20–30, 25–35, 35–50 and ≥ 50 mg/kg, respectively. In total, 586 patients received treatment; 299 (51%) were aged &lt;16 years, of whom 154 were treated with DSX. Baseline demographics and changes in LIC and serum ferritin after 1 year of treatment are shown in the table; data are presented as mean ± SD (standard deviation). DSX produced a fall in LIC in all age groups. A more moderate reduction in LIC occurred in patients aged &lt;6 years despite the administration of an average dose of 21.9 mg/kg in this subgroup; these patients had the highest mean transfusional iron intake. The results strongly suggest that transfusional iron intake is the major factor in determining response and should be considered carefully when dosing iron chelators in children. In those with high transfusion requirements, a dose of 30 mg/kg may be considered. DSX DFO EOS = end of study; SF = serum ferritin; aAll patients with a baseline and EOS LIC assessment Age at baseline, years &lt;6 (n=30) 6–11 (n=67) 12–15 (n=57) &lt;6 (n=28) 6–11 (n=68) 12–15 (n=49) Female: male, n 12:18 35:32 35:22 9:19 33:35 30:19 Average daily dose, mg/kg 21.9 ± 7.61 21.1 ± 8.49 18.0 ± 9.00 43.6 ± 9.17 42.5 ± 9.11 43.5 ± 9.62 Baseline LICa, mg Fe/g dw 13.2 ± 7.4 15.2 ± 10.6 12.4 ± 10.5 12.6 ± 6.0 13.2 ± 9.4 13.3 ± 10.4 EOS LICa, mg Fe/g dw 12.1 ± 4.4 11.1 ± 7.7 9.6 ± 7.0 8.8 ± 3.8 10.6 ± 7.4 9.8 ± 6.6 Baseline SF, ng/mL 2479 ± 843 3058 ± 1834 2813 ± 1567 2260 ± 874 2745 ± 1633 2847 ± 1507 EOS SF, ng/mL 2791 ± 1066 2710 ± 1526 2787 ± 1494 1774 ± 769 2439 ± 1356 2495 ± 1529 Transfusional iron intakea, mg/kg/day 0.48 ± 0.11 0.43 ± 0.09 0.37 ± 0.10 0.47 ± 0.12 0.44 ± 0.12 0.40 ± 0.10 DSX was well tolerated in children as young as 2 years of age at all dose levels, with a safety profile similar to that observed in adults. The most common adverse events (AEs) with a suspected relationship to DSX were abdominal pain, nausea, vomiting, diarrhea and skin rash. Of 154 pediatric patients who received DSX, 5 (3.2%) discontinued due to suspected drug-related AEs. There was no treatment-related neutropenia, agranulocytosis or arthralgia. Sexual development proceeded normally with no differences between the treatment groups. DSX has a safety profile that is compatible with long-term use in children as young as 2 years and is generally well tolerated at doses as high as 30 mg/kg in these heavily transfused patients.

Long-Term Effects of Deferasirox (Exjade®, ICL670) on Serum Ferritin: Outcome of Dose Adjustments in Achieving Maintenance or Reduction in Body Iron Stores.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1769-1769 ◽  
Author(s):  
J.B. Porter ◽  
A. Cohen ◽  
L. Agaoglu ◽  
A. Ganser ◽  
M.D. Cappellini ◽  
...  
Keyword(s):  
Serum Ferritin ◽  
Iron Concentration ◽  
Extension Phase ◽  
Long Term Effects ◽  
Liver Iron ◽  
Body Iron ◽  
The Core ◽  
Core Phase ◽  
The Impact

Abstract During 1-year core phases of two deferasirox trials, doses were initially assigned by baseline liver iron concentration (LIC). In these regularly transfused patients (mean iron intake 0.37 mg/kg/day), a clear dose response was observed: deferasirox 20/30 mg/kg/day effectively maintained/reduced body iron, 10 mg/kg/day maintained body iron in patients with low transfusion rates, whereas 5 mg/kg/day removed less iron than added by ongoing transfusions. This post-hoc analysis evaluates the impact on serum ferritin (SF) of dose increases during the extension phases, in patients who initially received 5/10 mg/kg/day. In patients who initially received deferasirox 5/10 mg/kg/day with increasing iron burden, doses were generally increased to 20–30 mg/kg/day during the first 6 months of the extension phase. Dose modifications for patients on 20/30 mg/kg/day were based on safety and efficacy parameters. SF was measured monthly. 480 patients (β-thalassemia, n=381; myelodysplastic syndromes, n=47; other anemias, n=52) initially received deferasirox 5/10 (n=119), 20 (n=136) or 30 (n=225) mg/kg/day in the core phase. Most continued on treatment in the extension phase, receiving deferasirox for a median of 2.6 years. Median baseline SF values in the three dose cohorts were 1932, 2527 and 4158 ng/mL, respectively. During the core and extension phases, SF levels decreased in patients who received deferasirox 30 mg/kg/day and were maintained in patients who received 20 mg/kg/day. In contrast, SF steadily increased in patients who initially received 5/10 mg/kg/day. Subsequent dose escalation during the extension phase generally resulted in decreased SF levels (see shaded area of Table), returning close to baseline by data cut-off. A similar pattern was observed irrespective of age or underlying anemia. Table. Median change from baseline in S:F (ng/ml) during deferasirox treatment of up to 2.6 years (n=480) A further 258 patients (deferoxamine arm in core phase) crossed over to deferasirox during the extension phase, receiving deferasirox for a median of 1.6 years. Comparable responses were observed in these patients versus those in the deferasirox cohort at corresponding doses. Conclusions: SF steadily decreased following dose increases in regularly transfused patients who initially received deferasirox 5/10 mg/kg/day. This analysis confirms that 30 mg/kg/day effectively reduces body iron over the long term, whereas 20 mg/kg/day is effective in maintaining body iron levels in regularly transfused patients. Deferasirox dose can therefore be effectively tailored depending on the goal of therapy (maintenance or reduction in body iron levels).

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

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3883-3883 ◽  
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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