scholarly journals Combination therapy with a T mprss6 RNA i‐therapeutic and the oral iron chelator deferiprone additively diminishes secondary iron overload in a mouse model of β‐thalassemia intermedia

2015 ◽  
Vol 90 (4) ◽  
pp. 310-313 ◽  
Author(s):  
Paul J. Schmidt ◽  
Tim Racie ◽  
Mark Westerman ◽  
Kevin Fitzgerald ◽  
James S. Butler ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Mouse Model ◽  
Iron Overload ◽  
Iron Chelator ◽  
Oral Iron ◽  
Thalassemia Intermedia ◽  
Secondary Iron Overload ◽  
Rna I ◽  
Oral Iron Chelator

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.

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

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.

An RNAi-Therapeutic Targeting Tmprss6, in Conjunction With Oral Chelator Therapy, Ameliorates Anemia and Additively Diminishes Secondary Iron Overload In a Mouse Model Of β-Thalassemia Intermedia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1019-1019
Author(s):  
Paul J Schmidt ◽  
Tim Racie ◽  
Jim S Butler ◽  
Kevin Fitzgerald ◽  
Mark D Fleming
Keyword(s):  
Mouse Model ◽  
Iron Overload ◽  
Iron Deposition ◽  
Iron Loading ◽  
Thalassemia Intermedia ◽  
Ineffective Erythropoiesis ◽  
Liver Iron ◽  
Therapeutic Targeting ◽  
Hepcidin Expression ◽  
Secondary Iron Overload

Abstract β-Thalassemias are a group of inherited blood disorders caused by loss of β-globin synthesis and are characterized by anemia, extramedullary hematopoiesis and ineffective erythropoiesis leading to secondary iron overload. Increased iron absorption is due to inappropriately low levels of the liver hormone, hepcidin (HAMP). The membrane serine protease Matriptase-2 (TMPRSS6) attenuates BMP-mediated HAMP induction by cleaving the BMP co-receptor, hemojuvelin (HJV). Previously, we demonstrated that an RNAi-therapeutic targeting Tmprss6 elevates hepcidin expression and reduces disease severity in the Hbbth3/+ mouse model of β-Thalassemia intermedia (Blood. 2013; 14;121(7):1200-8). To further interrogate the efficacy of this therapeutic approach, Hbbth3/+ animals were treated with a siRNA directed against Tmprss6 on a replete 50ppm iron diet, a low iron diet (3-5ppm iron) or a 50ppm iron diet containing deferiprone. Systemic administration of an siRNA directed against Tmprss6 in the three diet conditions leads to significant inhibition of Tmprss6 mRNA in the livers of Hbbth3/+ mice with concomitant elevation in hepcidin expression. In correspondence with earlier studies, we demonstrate here that Tmprss6 silencing in animals under each of the three diet regimens leads to a significant improvement in the anemia of Hbbth3/+ mice as evidenced by increased total hemoglobin. Furthermore, hallmarks of ineffective erythropoiesis, including splenomegaly and reticulocytosis, were decreased in all Tmprss6 silenced Hbbth3/+ animals. If untreated, excessive iron loading in humans with β-Thalassemia leads to tissue iron deposition and eventual organ damage and failure. Importantly, here we demonstrate that the total body iron burden of Hbbth3/+ mice, as assessed by non-heme liver iron, is decreased by almost 30% in animals chelated with oral deferiprone and treated with Tmprss6 siRNA. A similar diminution of iron deposition is not evident in animals on a low iron diet or in mice fed deferiprone alone. Taken together, this data suggest that siRNA suppression of Tmprss6, in conjunction with chelation therapy, may provide an improved modality for treatment of the anemia and secondary iron loading seen in hemoglobinopathies such as β-Thalassemia. Disclosures: Racie: Alnylam Pharmaceutical, Inc: Employment. Butler:Alnylam Pharmaceutical, Inc: Employment. Fitzgerald:Alnylam: Employment. Fleming:Alnylam Pharmaceutical, Inc: Research Funding.

scholarly journals Zinc concentration in patients with iron overload receiving oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one or desferrioxamine.

1994 ◽  
Vol 47 (7) ◽  
pp. 657-660 ◽  
Author(s):  
F N al-Refaie ◽  
B Wonke ◽  
D G Wickens ◽  
Y Aydinok ◽  
A Fielding ◽  
...  
Keyword(s):  
Iron Overload ◽  
Zinc Concentration ◽  
Iron Chelator ◽  
Oral Iron ◽  
Oral Iron Chelator
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