Long-term treatment of transfusional iron overload with the oral iron chelator deferiprone (L1): a Dutch multicenter trial

1996 ◽  
Vol 73 (5) ◽  
pp. 247-252 ◽  
Author(s):  
M. J. Kersten ◽  
R. Lange ◽  
M. E. P. Smeets ◽  
G. Vreugdenhil ◽  
K. J. Roozendaal ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Chelator ◽  
Multicenter Trial ◽  
Term Treatment ◽  
Oral Iron ◽  
Long Term Treatment ◽  
Oral Iron Chelator

Long-Term Safety and Tolerability of the Once-Daily, Oral Iron Chelator Deferasirox (Exjade®, ICL670) in Patients with Transfusional Iron Overload.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1768-1768 ◽  
Author(s):  
M.D. Cappellini ◽  
P. Giardina ◽  
J. Porter ◽  
T. Coates ◽  
M.G. Della Porta ◽  
...  
Keyword(s):  
Safety Data ◽  
Iron Chelator ◽  
Oral Iron ◽  
Tolerability Profile ◽  
The Core ◽  
Long Term Treatment ◽  
Adults And Children ◽  
Core Phase ◽  
Oral Iron Chelator

Abstract Introduction: The safety and tolerability profile of the oral iron chelator deferasirox has been established in five comprehensive trials (with a 1-year core phase) in adults and children with a range of transfusion-dependent anemias. Following completion of the core phase, pts entered an extension phase that will last for 4 years. This analysis presents cumulative long-term safety data during deferasirox treatment. Methods: Safety was assessed monthly, primarily by evaluating the incidence and type of adverse events (AEs) and measuring laboratory parameters. Results: A total of 1033 pts have received deferasirox: 703 initially received it during the core phases (deferasirox cohort) and 330, who initially received deferoxamine (DFO), crossed over to deferasirox in the extension phases (crossover cohort); 433 (41.9%) were pediatric pts aged 2-<16 years (289 and 144 in the deferasirox and crossover cohorts, respectively). Underlying disorders were: β-thalassemia (n=749), sickle cell disease (n=185), myelodysplastic syndromes (n=47), Diamond-Blackfan anemia (n=30), other anemias (n=22). To date, deferasirox has been administered for a median of 2.5 and 1.5 years in the deferasirox and crossover cohorts, with mean doses during treatment of 20.5 and 21.0 mg/kg/day, respectively. Crossover pts had previously received a mean DFO dose of 42.2 mg/kg/day. The reasons for discontinuation across both the core and extension phases in pts receiving deferasirox were: AEs (n=72; 7.0%), consent withdrawal (n=62, 6.0%), unsatisfactory therapeutic effect (n=29, 2.8%), other (n=37, 3.6%). Fifteen deaths (1.5%) occurred during deferasirox treatment, all considered unrelated to study drug by the Program Safety Board (one was reported as possibly related by an investigator). Drug-related AEs during deferasirox treatment were generally transient and of mild to moderate severity (Table). The AE pattern and incidence rates were comparable across all ages and underlying anemias, and in the deferasirox and crossover cohorts. Most common (>4% overall) drug-related AEs during deferasirox treatment (median 1.5–2.5 years; n=1033) AE Frequency, n (% of all pts) Severity, n (% of all pts) Mild Moderate Severe Nausea 99 (9.6) 85 (8.2) 12 (1.2) 2 (0.2) Diarrhea 91 (8.8) 71 (6.9) 18 (1.7) 2 (0.2) Abd pain 52 (5.0) 37 (3.6) 11 (1.1) 4 (0.4) Vomiting 49 (4.7) 40 (3.9) 8 (0.8) 1 (0.1) Rash 49 (4.7) 29 (2.8) 16 (1.5) 4 (0.4) Upper abd pain 44 (4.3) 34 (3.3) 9 (0.9) 1 (0.1) During the extension phases there were no changes in markers of liver or renal function that were consistently or significantly different from the core study. Ten pts (1.0%) had urinary total protein/creatinine ratio >1.0 at 2 consecutive visits. There have been no cases of progressive increases in serum creatinine, indicative of renal insufficiency or failure. Physical and sexual development proceeded normally in all pediatric pts. Conclusions: The safety and tolerability of deferasirox in pts receiving up to 2.5 years of treatment was similar to that observed during the 1-year core trials, with most AEs being mild, transient and easily manageable. These data demonstrate that long-term treatment with deferasirox is generally well tolerated in adults and children with a variety of transfusion-dependent anemias.

Iron Parameters in 84 MDS Patients Enrolled in a Deferasirox (Exjade®, ICL670) Multicenter Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4847-4847 ◽  
Author(s):  
Alan F. List ◽  
Jason Esposito ◽  
Jodie Decker ◽  
Maria R. Baer ◽  
Bayard Powell ◽  
...  
Keyword(s):  
Iron Overload ◽  
Creatinine Clearance ◽  
Serum Ferritin ◽  
Serum Iron ◽  
Transferrin Saturation ◽  
Iron Chelator ◽  
Oral Iron ◽  
Calculated Creatinine Clearance ◽  
Oral Iron Chelator

Abstract Introduction: Recent reviews indicate that transfusional hemosiderosis may be associated with an increased risk of mortality in lower-risk pts with MDS. This trial is designed to evaluate the efficacy and long-term safety of deferasirox (Exjade®, ICL670) in MDS. Deferasirox is an oral iron chelator approved for use in pts with transfusional iron overload. Methods: This is a Phase II, open-label, 3-yr clinical trial in 55 US centers, enrolling 150 pts (aged ≥18 years) with Low- or Int-1-risk MDS (by IPSS criteria) and transfusional iron overload (serum ferritin ≥1000 ng/mL and &gt;20 units RBC transfusions). Deferasirox dosing is 20–30 mg/kg/day. Serum ferritin, iron, transferrin and transferrin saturation are being assessed at screening and monthly in yr 1, then quarterly in yrs 2 and 3, while labile plasma iron (LPI) is assessed quarterly in yr 1. In addition, creatinine, calculated creatinine clearance, echocardiograms and endocrine and hematological status are being assessed. This report describes baseline data in these pts. Results: As of June 2006, 84 pts have enrolled. Demographic data are available from 79 pts: median age 71 years (range 47–87); sex (52 male, 27 female); ethnicity (74 Caucasian, 2 Black, 2 Hispanic, 1 Oriental); and IPSS Risk Group (Low: 22 pts; Int-1: 56 pts). Iron status is summarized in the table: Parameter n Mean ± SD Median Range Normal range n/a, not applicable Serum ferritin,μg/L 84 3779 ± 4070 2951 1160–36280 12–370 Serum iron, μg/dL 84 205 ± 64 201 48–409 37–180 Transferrin, mg/dL 82 153 ± 31 152 83–244 190–375 Transferrin saturation, % 83 85 ± 15 91 20–94 15–50 LPI, μmol/L 38 0.52 ± 0.63 0.25 0–2.9 0 Total transfusions, n 78 63.3 ± 66.3 41.5 14–435 n/a Years of transfusion 75 3.4 ± 1.9 3 1–12 n/a Baseline concurrent therapies: 5-azacytidine (Vidaza): 5 pts; lenalidomide (Revlimid): 1 pt. Calculated creatinine clearance: normal (&gt;80 mL/min): 37 pts; mildly abnormal (51–80 mL/min): 30 pts; moderately abnormal (30–50 mL/min): 9 pts. Hematological parameters: Anemia was present in all pts; other cytopenias included: neutropenia (&lt;1800/μL): 13 pts, thrombocytopenia (&lt;100,000/μL): 15 pts; neutropenia and thrombocytopenia: 12 pts. A total of 53 pts had received chelation prior to enrolling: 51 deferoxamine (Desferal®); and 2 deferasirox. Conclusions: Despite the prior availability of deferoxamine, these baseline data demonstrate significant levels of iron overload among transfused pts with myelodysplasia. Serum iron, ferritin and LPI are all well above the clinically significant thresholds associated with increased complications. Since recent data has suggested that iron overload may be a poor prognostic indicator in MDS, increased attention to maintaining appropriate iron balance is warranted. The recent availability of an oral iron chelator may be more acceptable to MDS pts and their physicians. This ongoing trial is designed to assess the long-term efficacy, safety, and clinical benefits of deferasirox in pts with MDS.

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

2005 ◽  
Vol 29 ◽  
pp. S67 ◽  
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

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

Blood ◽  
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.

scholarly journals Iron-balance and dose-response studies of the oral iron chelator 1,2- dimethyl-3-hydroxypyrid-4-one (L1) in iron-loaded patients with sickle cell disease

Blood ◽  
1994 ◽  
Vol 83 (8) ◽  
pp. 2329-2333 ◽  
Author(s):  
AF Collins ◽  
FF Fassos ◽  
S Stobie ◽  
N Lewis ◽  
D Shaw ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Iron Chelator ◽  
Total Iron ◽  
Oral Iron ◽  
Cell Disease ◽  
The Mean ◽  
Iron Excretion ◽  
Oral Iron Chelator

Several life-threatening complications of the common disorder sickle cell disease require management with red blood cell transfusions and, hence, long-term iron-chelating therapy. The efficacy of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) has not previously been determined in patients with sickle cell disease. We compared the efficacy of L1 to that of standard-dose subcutaneous deferoxamine in four regularly transfused patients with homozygous sickle cell disease, who had evidence of severe iron overload and a history of poor compliance with deferoxamine. Determination of 24-hour urinary iron excretion conducted over 5 days immediately after transfusion showed that the mean daily urinary iron excretion induced by L1 at 75 mg/kg/d (0.48 +/- 0.23 mg/kg) was equivalent to that induced by deferoxamine at 50 mg/kg/d (0.39 +/- 0.06 mg/kg). In two of three patients studied, a significant (P < .025) increase in mean daily urinary iron excretion was achieved when the dose of L1 was increased to 100 mg/kg/d. Total iron balance studies, which quantitated both urinary and stool iron excretion on L1 and deferoxamine, determined that mean total daily iron excretion induced by deferoxamine (0.88 +/- 0.05 mg/kg) was significantly greater (P < .05) than that induced by L1 (0.53 +/- 0.17 mg/kg), attributable to the significantly greater stool iron excretion during deferoxamine treatment (0.50 +/- 0.16 mg/kg/d) compared with that measured during L1 treatment (0.12 +/- 0.08 mg/kg/d, P < .01). Stool iron excretion accounted for a significantly greater percentage of total iron excretion during deferoxamine treatment (59% +/- 20%) than during L1 treatment (23% +/- 14%, P < .01). These iron balance studies are the first to compare total iron excretion induced by L1 with that achieved by deferoxamine. They demonstrate that the mean total daily iron excretion during L1 treatment (0.53 +/- 0.17 mg/kg) is sufficient to maintain net negative iron balance in most regularly transfused patients with sickle cell disease. Because long-term compliance with L1 has been shown previously to be superior to that with deferoxamine in patients with homozygous beta-thalassemia, the use of L1 should increase the long-term effectiveness of iron chelation in patients with sickle cell disease.

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

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3840-3840 ◽  
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&lt;0.0001). The last patient’s last visit will be in June 2006. Age 2 to &lt;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.

Equivalence of AutoCPAP and Fixed CPAP in the Long-term Treatment of Obstructive Sleep Apnea Syndrome: A Randomized, Controlled Multicenter Trial

CHEST Journal ◽  
2010 ◽  
Vol 138 (4) ◽  
pp. 886A ◽  
Author(s):  
Konrad E. Bloch ◽  
Tsogyal D. Latshang ◽  
Yvonne Nussbaumer-Ochsner ◽  
Malcolm Kohler ◽  
Robert Thurnheer ◽  
...  
Keyword(s):  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Sleep Apnea Syndrome ◽  
Multicenter Trial ◽  
Term Treatment ◽  
Randomized Controlled ◽  
Obstructive Sleep ◽  
Long Term Treatment ◽  
Apnea Syndrome
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