Efficacy and Safety of Deferasirox (Exjade®) in Patients with Transfusion- Dependent Anemias: Preliminary Results From the First, Retrospective, Multicenter Brazilian Study.

Abstract Abstract 5096 Background Deferasirox is a once-daily oral iron chelator with established dose-dependent efficacy for treating transfusional iron overload. The retrospective multicenter Brazilian trial included patients (pts) from 14 sites of 10 states with a variety of transfusion-dependent anemias and was designed to evaluate the efficacy and safety of fixed starting doses of deferasirox based on transfusion history, with subsequent dose titration based on serum ferritin (SF) trends. Data were available from 105 eligible pts at 6 months of treatment and 73 pts from 1-year follow-up period. Methods Pts (aged ≥ 2 yrs) had transfusion-dependent anemia with a history of multiple transfusions (>20 transfusions) and/or SF levels ≥ 1000 ng/mL and serum creatinine level < the upper limit of normal (ULN). Deferasirox starting dose was 10-30mg/kg/day depending on transfusion requirements and subsequent dose adjustments of 5-10 mg/Kg/day (range 0–35 mg/kg/d) were done every 3 months based on changes in SF and safety parameters. Efficacy was assessed monthly by measuring change from baseline in SF levels. Safety was evaluated on a monthly basis according to the incidence and type of adverse events and measurement of laboratory parameters, including serum creatinine and liver enzyme levels. Results 105 pts (40 M, 65 F; mean age 25.0±16.6 yrs) were enrolled; 46% (n=48) aged <20 yrs; 54% Afro-descendant (n=57). Underlying anemias were: sickle cell disease (n=59), β-thalassemia (n=32), myelodysplastic syndromes (n=6) and other conditions associated with anemia (n=8). Most pts (79%, n=83) had received > 40 units of red blood cell (RBC); 71.5% (n=75) were on regular RBC transfusion, 56% of the pts required < 2 RBC units/month and 44% between 2 and 4 RBC units/month. Only 63% (n=66) had received prior chelation therapy: deferoxamine (DFO; 51.4%) or DFO/deferiprone combination (11.4%). Sixty-four (61%) pts started on 20 mg/kg/d and 41(39%) > 20-30 mg/kg/d, 15.2% of pts had dose increases at a median of 24 weeks after treatment initiation. Mean ± SD SF levels (μg/L) did significantly reduce at 6 months and 12 months compared to baseline (BL) [from 3132.14 ± 2237.47 to 2784.25 ± 1969.7 at 6 months (p=0.0001) and 2327.46 ± 1873.8 at 12 months (p=0.005)]. The proportion of patients with SF levels < 2000, 2000-3000 and > 3000 μg/L from BL to 6 and 12 months by percentage of patients changed from 36% to 47.5% and 52%; from 26% to 26.5% and 24.5%; from 38% to 26% and 23%, respectively. No patient discontinued the treatment. No death was reported by the investigators during the study. The most common drug-related (investigator-assessed) AEs were mild, transient diarrhea (n=15; 14.3%), rash (n=5; 4.7%), nausea (n=9; 8.5%) and headache (n=6; 5.7%). Seven pts (6.6%) had serum creatinine value >33% above BL on two consecutive visits, 3 (2.8%) of whom had creatinine increases above the ULN; there were no progressive increases or renal failure. Eleven (10.5%) pts had an increase in alanine aminotransferase < 5x ULN but no one experience increases ≥ 5x ULN; levels were already elevated in all of them. Conclusions This first multicenter Brazilian study confirms deferasirox efficacy in achieving a reduction of iron load across a wide range of pts with transfusion-related iron overload. It also supports the clinical approach to fixed starting dose of deferasirox based on iron intake from ongoing blood transfusions and current iron burden with subsequent individual dose titration every 3 months according to SF trends and safety markers. Deferasirox was generally well tolerated in pediatric and adult pts with a safety profile consistent with data from previous clinical trials. The availability of deferasirox as a once-daily oral iron chelator would potentially facilitate improved compliance, and thereby reduce morbidity and mortality from iron overload. Disclosures No relevant conflicts of interest to declare.

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Deferasirox for the Treatment of Transfusional Iron Overload In Sickle Cell Anemia: a 2-Yr Prospective Study

Blood ◽

10.1182/blood.v116.21.5148.5148 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5148-5148

Author(s):

Rodolfo Cancado ◽

Maria Cristina Olivato ◽

Paula Bruniera ◽

Murilo Rezende Melo ◽

Carlos Chiattone

Keyword(s):

Serum Creatinine ◽

Iron Overload ◽

Sickle Cell ◽

Iron Chelator ◽

Left Ventricular ◽

Oral Iron ◽

Left Ventricular Ejection ◽

Once Daily ◽

Body Iron ◽

Oral Iron Chelator

Abstract Abstract 5148 Background: Majority of patients with sickle cell disease receive repeated blood transfusions by adulthood. Because the body has no physiological mechanism to actively excrete excess iron, chelation therapy is important for the management of iron overload and its complications, including iron deposition into the liver, heart and endocrine organs, eventual death. Deferasirox (DFX) is a once-daily, oral iron chelator that is approved as first-line treatment of chronic transfusional iron overload. Its safety, tolerability and efficacy in reducing body iron burden have been demonstrated in patients with β-thalassaemia major and in other chronic transfusion-dependent anaemias, including SCD. Aims and Methods: Objectives of this prospective, non-randomised, phase IV trial were to evaluate the iron overload status, before and after two year-treatment with DFX, using liver iron concentration [LIC, mg/d dry weight (dw)] by magnetic resonance imaging (MRI) hepatic, MRI cardiac (Cardiac T2*, ms), serum ferritin (SF, μ g/L), and to evaluate the safety and tolerability of DFX. Results: A total of 31 patients with SCD and iron overload, defined as the use of ≥ 20 units of RBC units and/or two SF levels ≥ 1000 μ g/L during the 6 months preceding enrollment, received starting dose of 20mg/kg/day of DFX. Efficacy was assessed monthly by measuring change from baseline in SF levels. Safety was evaluated on a monthly basis according to the incidence and type of adverse events and measurement of laboratory parameters, including serum creatinine and liver enzyme levels. Two patients discontinued treatment at 8 and 9 months, due to pregnancy and moving to other city, respectively. One patient died at 18 months due to pulmonary infection and hemorrhagic stroke. DFX was interrupted in 3 patients due to confirmed SF levels <500 μ g/L at 18-month period of treatment and DFX was not reinstated in none of them during the final 6 months of study. Twenty-five patients completed 2-year treatment. Mean ± SD age 26.9 ± 12.5y; 84% female, 90% afrodescendent, 61.3% on regular blood transfusion; median (range) DFX dose over 24 months and DFX exposure were 20 mg/kg/day (15-25) and 90.5 weeks (35.6-98.0), respectively. Mean SF level (μ g/L) did not significantly reduced at 12 months (p=0.052) but significantly dropped at 24 months compared to baseline [from 2344.6 to 1986.3 (p=0.040)]. Mean ± SD LIC significantly dropped at 12 months and at 24 months compared to baseline [from 13.0 ± 5.4 to 10.4 ± 6.3 (p=0.001) and to 9.3 ± 5.7 (p<0.001), respectively]. The proportion of patients with LIC levels (mg/g dw) ≤7.0, >7.0- ≤14.0 and >14.0 from baseline to 24 months by percentage of patients changed from 13.6% to 44.0%, 40.9% to 44.0% and 45.5% to 12.0%, respectively. In all patients, Cardiac T2* was normal (> 20 ms) at baseline, 12 and 24 months of treatment. There was no significant difference between left ventricular ejection fraction values at baseline and after 12 months but this parameter significantly increased at 24 months of treatment compared to baseline [from 62.2 ± 6.0 to 64.6 ± 6.2 (p=0.02)]. The most common drug-related AEs were mild, transient diarrhea (7 pts), headache (7), nausea (5), vomiting (3), skin rash (2), increases in ALT (2), serum creatinine increases that exceeded the ULN (2). No patient experienced progressive increases in serum creatinine or renal failure. Conclusions: Our data confirms that deferasirox is effective in reducing body iron burden in transfused patients with SCD, well tolerated in pediatric and adult patients and with a clinically manageable safety profile. The availability of deferasirox as a once-daily, oral iron chelator would potentially facilitate improved compliance, and thereby reduce morbidity and mortality from iron overload. Disclosures: No relevant conflicts of interest to declare.

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A Phase II Study with ICL670 (Exjade®), a Once-Daily Oral Iron Chelator, in Patients with Various Transfusion-Dependent Anemias and Iron Overload.

Blood ◽

10.1182/blood.v104.11.3193.3193 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3193-3193 ◽

Cited By ~ 13

Author(s):

John Porter ◽

Elliot Vichinsky ◽

Christian Rose ◽

Antonio Piga ◽

Nancy Olivieri ◽

...

Keyword(s):

Iron Overload ◽

Phase Ii ◽

Quantum Interference ◽

Safety Data ◽

Iron Chelator ◽

Oral Iron ◽

Efficacy And Safety ◽

Liver Iron ◽

Once Daily ◽

Oral Iron Chelator

Abstract Iron overload is a potentially life-threatening medical problem for patients with chronic transfusion-dependent anemias who cannot receive adequate iron chelation with existing therapies. ICL670 (deferasirox) is an investigational, tridentate, once-daily oral iron chelator that has demonstrated high iron binding potency and selectivity. The efficacy and safety of ICL670 is being investigated across a broad range of patient ages in a Phase II multicenter study in 7 countries in patients who are transfusion-dependent due to a variety of chronic anemias. The study population includes patients with various rare chronic anemias (n=98) and β-thalassemia patients who cannot be adequately treated with deferoxamine (n=86). The rare anemia category comprises 47 patients with myelodysplastic syndrome, 28 with Diamond-Blackfan anemia and 23 with other anemias of diverse etiologies. Between March and November 2003, 184 patients were enrolled in the following countries: Italy (57), US (36), France (20), UK (20), Canada (18), Germany (17), Belgium (16). Based on liver iron content (LIC) at baseline (2–3, >3–7, >7–14 and >14 mg Fe/g dw), patients were allocated to receive once daily oral ICL670 at doses of 5, 10, 20 or 30 mg/kg, respectively. Treatment was for one year initially, to be followed by an extension phase. LIC, the primary outcome measure, was assessed at baseline by liver biopsy or, when biopsy was contraindicated and also in some pediatric patients, non-invasively by magnetic susceptometry using a Superconducting QUantum Interference Device (SQUID). LIC will be reassessed after 12 months of therapy in each patient using the same methodology as at baseline. Liver biopsies are analyzed at a single center (Rennes, France) and 3 centers (Turin, Italy; Hamburg, Germany; Oakland, US) are performing SQUID assessments. At baseline, median (25–75th percentiles) LIC was 19.6 mg Fe/g dw (15.1–28.8) by biopsy and 9.1 (6.8–13.3) in those patients assessed by SQUID. Baseline patient demographics and disease characteristics (median values) are summarized in the table. ICL670 has been generally well tolerated. As of 30 April, 28 patients, predominantly with rare anemias, had discontinued the study due mainly to complications of the underlying disease. The key efficacy and safety data from the initial 12 months of therapy will be available for presentation in early December 2004. Disease group (by initial dose) Rare anemias (n = 98) β-thalassemia (n = 86) ≤ 10 mg/kg n = 16 20 mg/kg n = 29 30 mg/kg n = 53 ≤ 10 mg/kg n = 10 20 mg/kg n = 23 30 mg/kg n = 53 Age (yrs) median 56 39 49 21 23 25 No. of ≥ pts 2 - <16 yrs 4 10 6 4 8 3 No. of ≥ pts 16 - <50 yrs 2 7 21 6 14 49 No. of ≥ pts 50yrs 10 12 26 0 1 1 No. of males/females 10/6 13/16 27/26 3/7 15/8 25/28 LIC (mg Fe/g dry weight) 4.3 9.7 21.8 4.3 9.7 23.1 No. of pts with biopsy/SQUID 2/14 7/22 43/10 6/4 13/10 49/4 Serum ferritin (ng/ml) 1568 2751 3661 2131 2951 4516

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P-113 The efficacy and tolerabilityof ICL670, a once-daily oral iron chelator, in patients with myelodysplastic syndrome (MDS) and iron overload

Leukemia Research ◽

10.1016/s0145-2126(05)80177-8 ◽

2005 ◽

Vol 29 ◽

pp. S67 ◽

Cited By ~ 10

Author(s):

N. Gattermann ◽

M. Cazzola ◽

P. Greenberg ◽

J. Maertens ◽

D. Soulieres ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Iron Overload ◽

Iron Chelator ◽

Oral Iron ◽

Once Daily ◽

Oral Iron Chelator

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Deferasirox (Exjade®, ICL670) Treatment of Inadequately Chelated β-Thalassemia Patients from the Middle East: The ESCALATOR Trial.

Blood ◽

10.1182/blood.v106.11.3840.3840 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3840-3840 ◽

Cited By ~ 1

Author(s):

Ali Taher ◽

Amal El-Beshlawy ◽

Abdullah Al Jefri ◽

Mohsen El Alfy ◽

Kusai Al Zir ◽

...

Keyword(s):

Iron Overload ◽

Chelation Therapy ◽

Iron Concentration ◽

Iron Chelator ◽

Oral Iron ◽

Study Cohort ◽

Liver Iron ◽

Transfusion Therapy ◽

Once Daily ◽

Oral Iron Chelator

Abstract Iron overload is a potentially life-threatening consequence of multiple blood transfusions. Effective iron chelation therapy reduces morbidity and saves lives. Many patients are unable to comply with current treatments, deferoxamine (DFO) or deferiprone (L1), because they cannot tolerate the parenteral infusion regimen required for DFO, because of adverse events (AEs), or because they do not respond to treatment. The objective of the ESCALATOR trial is to evaluate the effectiveness of deferasirox, an investigational once-daily oral iron chelator in advanced clinical development, in reducing liver iron concentration (LIC) in patients with β-thalassemia unable to be properly treated with DFO and/or L1. During a 1-year treatment period, patients will receive deferasirox at a daily dose of 20 mg/kg. Reduction of LIC is the primary endpoint, as assessed by biopsy at baseline and study end. Secondary efficacy variables include serum ferritin (SF) and other potential surrogate markers of iron overload such as concentration of labile plasma iron (LPI) in a subgroup of patients. Safety assessments include AEs and comprehensive laboratory evaluations. To date, 232 patients have initiated treatment at seven centers in five countries (Egypt, Saudi Arabia, Lebanon, Oman, Syria). Demographics, relevant medical history and baseline iron burden parameters are described in the table. Importantly, baseline SF values were significantly correlated with LIC (R=0.63; P<0.0001). The last patient’s last visit will be in June 2006. Age 2 to <16 years (n=159) Age ≥16 years (n=73) All patients (n=232) Mean ± SD; †n=14 Female:male, n 79:80 35:38 114:118 Race (caucasian:oriental:other), n 59:81:19 11:41:21 70:122:40 BMI*, kg/m2 17.4 ± 2.6 21.6 ± 3.2 18.7 ± 3.4 Weight*, kg 29.4 ± 9.9 54.7 ± 9.7 37.3 ± 15.3 Hepatitis B or C, n 43 29 72 Splenectomy, n 46 53 99 Transfusions in previous year*, n 15.5 ± 4.5 14.3 ± 3.7 15.1 ± 4.3 Total volume transfused in previous year*, mL 5265 ± 2469 7446 ± 2953 5873 ± 2784 Years on chelation therapy*, n 6.2 ± 3.5 12.7 ± 4.8 8.2 ± 4.9 Proportion of life on transfusion therapy*, % 89.3 ± 13.9 89.0 ± 14.1 89.2 ± 14.0 Liver pathology grading (modified HAI scale) Grade 0–6 143 64 207 Grade 7–12 4 0 4 Grade 13–18 0 0 0 LIC, mg Fe/g dw Mean ± SD 17.1 ± 8.5 20.0 ± 10.0 18.0 ± 9.1 Median (min, max) 16.6 (2.9, 38.2) 19.0 (2.9, 48.9) 17.5 (2.9, 48.9) SF, ng/mL Mean ± SD 3957 ± 2342 4564 ± 4117 4148 ± 3019 Median (min, max) 3356 (914, 13539) 3335 (956, 23017) 3346 (914, 23017) LPI†,μmol/L Mean ± SD - - 1.03 ± 0.80 Median (min, max) - - 0.82 (0, 2.65) The ESCALATOR study cohort is a highly challenging population with varied chelation response and transfusion history. The magnitude of LIC and SF, which were well correlated, reflects the severity of iron overload in patients unable to maintain adequate chelation using DFO or L1. This study will provide important insights into the clinical management of iron overload with the well tolerated, once-daily oral iron chelator deferasirox in this difficult-to-treat population.

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Efficacy and Safety of Deferasirox (Exjade®) in Patients with Transfusion- Dependent Anemias: 1-Year Results from the Large, Prospective, Multicenter EPIC Study

Blood ◽

10.1182/blood.v112.11.3875.3875 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3875-3875 ◽

Cited By ~ 1

Author(s):

Maria Domenica Cappellini ◽

Amal El-Beshlawy ◽

Antonis Kattamis ◽

Jong Wook Lee ◽

John F Seymour ◽

...

Keyword(s):

Iron Overload ◽

Iron Chelator ◽

Dose Titration ◽

Blood Transfusions ◽

Average Dose ◽

Efficacy And Safety ◽

Iron Intake ◽

Wide Range ◽

Starting Dose ◽

Median Change

Abstract Background: Deferasirox is a once-daily oral iron chelator with established dose-dependent efficacy for treating transfusional iron overload. In registration trials, the starting dose was based on baseline liver iron concentration (LIC). The prospective multicenter EPIC trial, the largest ever conducted for an iron chelator, included patients (pts) with a variety of transfusion-dependent anemias and was designed to evaluate the efficacy and safety of fixed starting doses of deferasirox based on transfusion history, with subsequent dose titration based on serum ferritin (SF) trends. One-year results are presented. Methods: Pts (aged ≥2 yrs) had transfusion-dependent anemia and SF levels ≥1000 ng/mL, or <1000 ng/mL with a history of multiple transfusions (>20 transfusions or >100 mL/kg of RBCs) and R2 MRI-confirmed LIC of >2 mg Fe/g dry weight (dw). Deferasirox starting dose was 20 mg/kg/d for pts receiving 2–4 blood units/mth. An initial dose of 10 or 30mg/kg/d was considered for pts receiving less or more frequent blood transfusions, respectively. Protocol-specified dose adjustments of 5–10 mg/kg/d (range 0–40 mg/kg/d) were done every 3 months based on SF trends and safety markers. Primary efficacy endpoint was SF change from baseline (BL) at 1 year. Results: 1744 pts (901 M, 843 F; mean age 30.6±23.3 yrs) were enrolled; 33.1% (n=577) aged <16 yrs. Underlying anemias were: β-thalassemia (n=1115), myelodysplastic syndromes (n=341), sickle cell disease (n=80), aplastic anemia (n=116) and other conditions associated with anemia (n=92). Pts received a mean of 17.8 transfusions and 159 mL/kg of blood in the previous year. 77% had received prior chelation therapy: deferoxamine (DFO; 58.6%), deferiprone (1.6%), DFO/deferiprone combination (16.7%) or other (0.3%). 1555 pts (89%) started on ≤20 mg/kg/d and 187 (11%) on >20 mg/kg/d. 39% of pts had dose increases at a median of 24 weeks after treatment initiation (range 2–53). Overall, median SF was significantly decreased from BL by 264 ng/mL after 1 year (P<0.0001) at an average actual received dose of 22.2±5.9 mg/kg/d. SF changes based on average dose the pts received throughout the course of the study are presented in Table 1. The extent of reduction in SF was reflective of dosage adjustments over the study. Table 1. Median change from BL in SF (ng/mL) and mean iron intake (mg/kg/day) by average actual dose BL End of study Over the study Average actual dose categories N Median SF (ng/mL) N Median change from BL in SF (ng/mL) P -value vs BL N Mean iron intake (mg/kg/day) <20 mg/kg/d 610 2608 586 −279 <0.0001 329 0.35 ≥20 – <30 mg/kg/d 984 3165 972 −198 0.0130 1141 0.43 ≥30 mg/kg/d 150 5048 149 −882 <0.0001 175 0.37 All pts 1744 3135 1707 −264 <0.0001 1645 0.41 1389 pts (79.6%) completed 1 year; reasons for discontinuation were adverse events (AEs; n=153; 8.8%), consent withdrawal (n=77; 4.4%), unsatisfactory therapeutic effect (n=20; 1.1%) and various other reasons (n=62; 3.6%); there were 31 (1.8%) drug related SAEs and 42 deaths, none assessed by investigators as treatment related. The most common drug-related (investigator-assessed) AEs were diarrhea (n=251; 14.4%), rash (n=174; 10.0%), nausea (n=135; 7.7%) and abdominal pain (n=97; 5.6%). 175 pts (10.0%) had serum creatinine value >33% above BL and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases. 13 (0.7%) had an increase in alanine aminotransferase >10×ULN on two consecutive visits; levels were already elevated in 11 pts. Conclusions: This large study confirms deferasirox efficacy in achieving a reduction of iron load across a wide range of pts with transfusion-related iron overload. It also supports the clinical approach to fixed starting dose of deferasirox based on iron intake from ongoing blood transfusions and current iron burden with subsequent individual dose titration every 3 months according to SF trends and safety markers. Deferasirox was generally well tolerated with a safety profile consistent with data from previous clinical trials.

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