Mitapivat Improves Transfusion Burden and Reduces Iron Overload in Thalassemic Mice

Abstract Mitapivat, an oral activator of pyruvate kinase (PK), was recently shown to improve b-thalassemic anemia with a reduction of ineffective erythropoiesis and an amelioration of b-thalassemic red cell features in a mouse model for b-thalassemia (Hbb 3th/+ mice).). These changes were also associated with a beneficial effect on iron homeostasis by modulation of duodenal DMT1 expression (Matte A et al JCI 2021). Two clinical studies have shown improvement of anemia and ineffective erythropoiesis with mitapivat treatment in patients with non-transfusion-dependent (NTD) thalassemia (Kuo et al. EHA 2021). Based on these results, Phase 3 studies in both NTD and TD thalassemia are currently on going. The objective of this preclinical study was to determine if treatment with mitapivat affects the length between transfusion of red blood cells (RBCs) and the liver iron concentration (LIC). Using a previously established murine model of RBCs transfusions (Park Y et al Blood 2020), in Hbb 3th/+ mice, we used Hb 10.5 g/dL as threshold for RBCs transfusion, with washed RBCs, at 40% Hct (400 uL total volume infused). The animals were divided into two groups: vehicle and mitapivat (50mg/Kg by gavage BID for up to 61 days).The length of the interval between transfusions increased in mitapivat treated compared to vehicle treated animals (transfusion interval: 13.8±1.0 days vs vehicle 10.5±1.0 days respectively n=4 and n=3). In both groups, the transfusion regimen induced a significant reduction in spleen weight/mouse weight ratio and in extramedullary erythropoiesis. We also found a significant reduction in liver iron content (LIC) in mitapivat treated compared to vehicle treated animals. We then evaluated the effects of mitapivat in combination with iron chelation using deferiprone (DFP,1.25 mg/mL, drinking water). Casu et al. have previously shown in the same mouse model for β-thal that DFP did not affect erythropoiesis. In the β-thal mice, we did not find negative effects on hematologic parameters when mitapivat (50 mg/Kg/d by gavage BID) was co-administrated with DFP for 28 days. LIC was reduced in mitapivat treated mice and in mitapivat +DFP treated β-thal mice was further decreased compared to vehicle treated animals. This allowed us to reduce DFP dosage from 1.25 to 0.8 mg/mL in mitapivat treated β-thal mice. These data show that in mouse model of transfused β-thalassemia, mitapivat increases the time interval between transfusions, reduces transfusion burden and allows a reduction of the dosing iron chelation with DFP. Thus, mitapivat might represent an interesting option in transfusion dependent β-thalassemic patients, being transfusion burden still an unmet need in this patient population. Disclosures Kosinski: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Dang: Agios Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. De Franceschi: F. Hoffmann-La Roche Ltd: Consultancy.

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The Oral Ferroportin Inhibitor VIT-2763 Improves Erythropoiesis without Interfering with Iron Chelation Therapy in a Mouse Model of β-Thalassemia

International Journal of Molecular Sciences ◽

10.3390/ijms22020873 ◽

2021 ◽

Vol 22 (2) ◽

pp. 873

Author(s):

Naja Nyffenegger ◽

Anna Flace ◽

Cédric Doucerain ◽

Franz Dürrenberger ◽

Vania Manolova

Keyword(s):

Mouse Model ◽

Iron Overload ◽

Chelation Therapy ◽

Iron Concentration ◽

Transferrin Saturation ◽

Iron Chelation ◽

Iron Chelator ◽

Liver Iron Concentration ◽

Ineffective Erythropoiesis ◽

Liver Iron

In β-thalassemia, ineffective erythropoiesis leads to anemia and systemic iron overload. The management of iron overload by chelation therapy is a standard of care. However, iron chelation does not improve the ineffective erythropoiesis. We recently showed that the oral ferroportin inhibitor VIT-2763 ameliorates anemia and erythropoiesis in the Hbbth3/+ mouse model of β-thalassemia. In this study, we investigated whether concurrent use of the iron chelator deferasirox (DFX) and the ferroportin inhibitor VIT-2763 causes any pharmacodynamic interactions in the Hbbth3/+ mouse model of β-thalassemia. Mice were treated with VIT-2763 or DFX alone or with the combination of both drugs once daily for three weeks. VIT-2763 alone or in combination with DFX improved anemia and erythropoiesis. VIT-2763 alone decreased serum iron and transferrin saturation (TSAT) but was not able to reduce the liver iron concentration. While DFX alone had no effect on TSAT and erythropoiesis, it significantly reduced the liver iron concentration alone and in the presence of VIT-2763. Our results clearly show that VIT-2763 does not interfere with the iron chelation efficacy of DFX. Furthermore, VIT-2763 retains its beneficial effects on improving ineffective erythropoiesis when combined with DFX in the Hbbth3/+ mouse model. In conclusion, co-administration of the oral ferroportin inhibitor VIT-2763 and the iron chelator DFX is feasible and might offer an opportunity to improve both ineffective erythropoiesis and iron overload in β-thalassemia.

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Hepcidin Peptidomimetics - Oral Efficacy in Pre-Clinical Disease Model of Iron Overload

Blood ◽

10.1182/blood-2020-141720 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 47-48

Author(s):

Roopa Taranath ◽

Gregory Bourne ◽

Jie Zhang ◽

Brian Frederick ◽

Tran T Tran ◽

...

Keyword(s):

Mouse Model ◽

Iron Overload ◽

Polycythemia Vera ◽

Serum Iron ◽

Iron Homeostasis ◽

Hereditary Hemochromatosis ◽

Iron Concentration ◽

Transferrin Saturation ◽

Private Company ◽

Liver Iron

Hepcidin peptidomimetics that are orally stable and systemically active will mark a paradigm change in management of blood disorders that exhibit aberrant iron homeostasis (e.g. hereditary hemochromatosis) and in conditions that can be influenced by modulating stressed iron homeostasis (e.g. polycythemia vera). Hepcidin modulates the iron exporter membrane protein ferroportin and is the master regulator of iron homeostasis in the body. Orally bioavailable "Minihepcidins" have been previously shown to be efficacious in lowering serum iron in mice when dosed peroral (PO) (Preza GC et. al., Journal of Clinical Investigation 2011). Here we describe hepcidin mimetic peptides that are metabolically stable in the gastrointestinal tract, systemically absorbed when delivered orally, and pharmacodynamically active in reducing serum iron parameters in pre-clinical models. Further, we also demonstrate improvement in disease parameters in a mouse model for hereditary hemochromatosis. The oral peptides, PN20076 and PN20089, have EC50 of 16.5 nM and 1.39 nM respectively in cell based ferroportin internalization assay (Table 1). In comparison EC50 was 67.8 nM for Hepcidin and 6.12 nM for PTG-300. (PTG-300 is an injectable hepcidin mimetic currently in Phase 2 clinical studies for polycythemia vera and hereditary hemochromatosis.) Oral stability of the peptides was evaluated in a panel of assays, including in vitro matrices simulating the gastric and intestinal conditions, and ex vivo matrices of serum/plasma from different species. Table 1 shows data for peptides PN20018, PN20076 and PN20089. PN20076 demonstrated extended stability in gastric and intestinal conditions, and degradation half-life of >24 hr in mouse plasma and 14.8 hr in rat serum. Based on their stability and potency data from the above battery of screening assays, the peptides were selected for in vivo evaluation in healthy mice to characterize their pharmacodynamic (PD) and pharmacokinetic (PK) properties. PN20076 and PN20089 showed equivalent PD response of reduction in serum iron concentration in wild type mice. After two successive PO doses of PN20076 or PN20089 approximately 24 hr apart, serum iron concentration was reduced from ~30 µM to ~10 µM (group averages), i.e. ~66% reduction, at 4.5 hr post-second dose for both peptides (Fig. 1). At 4.5 hr post-dose, the serum concentration of PN20076 was ~262 nM. PN20076 was further evaluated for its effect in lowering iron overload in a mouse model for hemochromatosis (HFE2-/- with homozygous deletion of hemojuvelin, a positive regulator of hepcidin expression). This mouse model is marked by hyper-absorption of dietary iron, higher transferrin saturation and deposition of excessive iron in liver, all manifestations of aberrant iron homeostasis caused by the genetic disruptions of the hepcidin-iron pathway. Liver iron accumulation was significantly prevented in groups treated with PN20076 once daily (QD) by PO administration for over two weeks, as compared to vehicle treated controls (Fig. 2). The reduction in non-heme iron concentration in liver homogenates (measured using a colorimetric iron assay) was statistically significant in the female group treated with PN20076. We have described orally stable and systemically active hepcidin mimetic peptides and demonstrated oral activity in preventing liver iron overload in hemochromatosis mice. The effective reduction of iron absorption from the diet and the steady state lowering of transferrin-saturation can potentially prevent tissue iron toxicity in hereditary hemochromatosis. Similarly, the sustained reduction of systemic iron levels with an oral hepcidin mimetic to control stressed iron homeostasis should reduce excessive erythrocytosis, a hallmark of polycythemia vera and other congenital and acquired erythropoietic disorders. Disclosures Bourne: Protagonist Therapeutics: Current Employment, Other: shareholder. Zhang:Protagonist Therapeutics: Current Employment, Other: shareholder. Frederick:Protagonist Therapeutics: Current Employment, Other: shareholder. Tran:Protagonist Therapeutics: Current Employment, Other: shareholder. Vengalam:Protagonist Therapeutics: Current Employment, Current equity holder in private company. McMahon:Protagonist Therapeutics: Current Employment, Other: shareholder. Huie:Protagonist Therapeutics: Current Employment, Other: shareholder. Ledet:Protagonist Therapeutics: Current Employment, Other: shareholder. Zhao:Protagonist Therapeutics: Current Employment, Other: shareholder. Tovera:Protagonist Therapeutics: Current Employment, Current equity holder in private company. Lee:Protagonist Therapeutics: Current Employment, Current equity holder in private company. Yang:Protagonist Therapeutics: Current Employment, Other: shareholder. Dion:Protagonist Therapeutics: Current Employment, Current equity holder in private company. Yuan:Protagonist Therapeutics: Current Employment, Other: shareholder. Zemede:Protagonist Therapeutics: Current Employment, Current equity holder in private company. Nguyen:Protagonist Therapeutics: Current Employment, Current equity holder in private company. Masjedizadeh:Protagonist Therapeutics: Current Employment, Current equity holder in private company. Cheng:Protagonist Therapeutics: Current Employment, Current equity holder in private company. Mattheakis:Protagonist Therapeutics: Current Employment, Current equity holder in private company. Liu:Protagonist Therapeutics: Current Employment, Current equity holder in private company. Smythe:Protagonist Therapeutics: Current Employment, Other: shareholder.

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Hepatocellular Carcinoma in β-Thalassemia Patients: Review of the Literature with Molecular Insight into Liver Carcinogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms19124070 ◽

2018 ◽

Vol 19 (12) ◽

pp. 4070 ◽

Cited By ~ 4

Author(s):

Antoine Finianos ◽

Charbel Matar ◽

Ali Taher

Keyword(s):

Hepatocellular Carcinoma ◽

Iron Overload ◽

Treatment Success ◽

Iron Concentration ◽

Iron Chelation ◽

Multicenter Studies ◽

Major Life ◽

Liver Iron ◽

Magnetic Resonance Imaging Mri ◽

Personalized Approach

With the continuing progress in managing patients with thalassemia, especially in the setting of iron overload and iron chelation, the life span of these patients is increasing, while concomitantly increasing incidences of many diseases that were less likely to show when survival was rather limited. Hepatocellular carcinoma (HCC) is a major life-threatening cancer that is becoming more frequently identified in this population of patients. The two established risk factors for the development of HCC in thalassemia include iron overload and viral hepatitis with or without cirrhosis. Increased iron burden is becoming a major HCC risk factor in this patient population, especially in those in the older age group. As such, screening thalassemia patients using liver iron concentration (LIC) measurement by means of magnetic resonance imaging (MRI) and liver ultrasound is strongly recommended for the early detection of iron overload and for implementation of early iron chelation in an attempt to prevent organ-damaging iron overload and possibly HCC. There remain lacking data on HCC treatment outcomes in patients who have thalassemia. However, a personalized approach tailored to each patient’s comorbidities is essential to treatment success. Multicenter studies investigating the long-term outcomes of currently available therapeutic options in the thalassemia realm, in addition to novel HCC therapeutic targets, are needed to further improve the prognosis of these patients.

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

Blood ◽

10.1182/blood-2010-11-316646 ◽

2011 ◽

Vol 118 (4) ◽

pp. 884-893 ◽

Cited By ~ 117

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.

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Does Gene Therapy in Beta Thalassemia Normalize Novel Markers of Ineffective Erythropoiesis and Iron Homeostasis?

Blood ◽

10.1182/blood-2019-129658 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 816-816 ◽

Cited By ~ 1

Author(s):

Alexis A. Thompson ◽

Tomas Ganz ◽

Mary Therese Forsyth ◽

Elizabeta Nemeth ◽

Sherif M. Badawy

Keyword(s):

Gene Therapy ◽

Stem Cell ◽

Iron Overload ◽

Serum Ferritin ◽

Research Funding ◽

Iron Homeostasis ◽

Beta Thalassemia ◽

Ineffective Erythropoiesis ◽

Liver Iron ◽

Equity Ownership

BACKGROUND: Ineffective erythropoiesis in thalassemia alters iron homeostasis, predisposing to systemic iron overload. Successful allogeneic hematopoietic stem cell transplantation (HSCT) in thalassemia major corrects anemia, should eliminate ineffective erythropoiesis (IE) and normalize iron homeostasis (IH). Whether gene therapy (GT) will fully correct IE and IH is not known. This cross-sectional observational study evaluated the iron status of patients with beta thalassemia following HSCT or GT, and compared them with cohorts of patients with thalassemia intermedia (TI) or transfusion-dependent thalassemia (TDT) using recently introduced biomarkers along with imaging studies and other clinical assessments to better understand and characterize IE and IH across groups. METHODS: We evaluated a convenience sample of 29 participants with beta thalassemia (median age 25 years, IQR 21-35; females 55%; Asian 52%). Participants in the HSCT (n=6) and GT (n=10) groups were evaluated on average 116.5 and 46.9 months following cell infusion, respectively. TDT patients (n= 9) were evaluated pre-transfusion and off iron chelation for at least 7 days, and TI (n=4) were un-transfused or not transfused in >3 years. Clinical lab assessments and MRI R2*/ T2* to assess heart and liver iron burden including post-processing, were performed using local clinical protocols. ELISAs for hepcidin, erythroferrone (Erfe) and GDF-15 were performed in a blinded manner. RESULTS: Median values for all IE and IH parameters tested were normal in the HSCT group, and were significantly lower than in all other groups. There were significant differences among all groups for hemoglobin (p=0.003), erythropoietin (Epo) (p=0.03), serum ferritin (SF) (p=0.01), transferrin (p=0.006), soluble transferrin receptor (sTfR) (p=0.02), serum hepcidin: serum ferritin (H:F) ratio (p=0.006), Erfe (p=0.001), GDF15 (p=0.003), and liver iron content (LIC) by MRI R2* (p=0.02). H:F ratio, a surrogate for predisposition to systemic iron loading, inversely correlated with Erfe (rs= -0.85, p<0.0001), GDF15 (rs= -0.69, p=0.0001) and liver R2* (rs= -0.66, p=0.0004). In a multivariate analysis, adjusted for gender and race, H:F ratio and Epo levels predicted Erfe and GDF15 (p=0.05 and p=0.06; p=0.01 and p=0.05), respectively. Even after excluding GT patients that are not transfusion independent (N=2), SF, Epo, sTfR and hepcidin remain abnormal in the GT group, and there were no significant differences in these parameters between GT and TDT. However, novel biomarkers of IH and IE suggested lower ineffective erythropoiesis in GT compared to TDT (median (IQR) Erfe, 12 (11.6-25.2) vs. 39.6 (24.5-54.7), p=0.03; GDF15, 1909.9 (1389-4431) vs. 8906 (4421-12331), p=0.02), respectively. Erfe and GDF15 were also lower in GT compared to TI, however these differences did not reach statistical significance. There were no differences in hepcidin, ferritin, or H:F by race, however Erfe and GDF15 were significantly lower in Asians compared to non-Asians (p=0.006 and p=0.02, respectively). CONCLUSION: Nearly 4 years post infusion, most subjects with TDT treated with GT are transfusion independent with near normal hemoglobin, however, studies in this limited cohort using conventional measures suggest IE and IH improve, particularly when transfusion support is no longer needed, however they remain abnormal compared to HSCT recipients, who using these parameters appear to be cured. STfR did not detect differences, however GDF15 and Erfe were more sensitive assays that could demonstrate significant improvement in IE and IH with GT compared to TDT. Contribution to IE by uncorrected stem cell populations post GT cannot be determined. Transduction enhancement and other recent improvements to GT may yield different results. Longitudinal studies are needed to determine if thalassemia patients treated with GT will have ongoing IE predisposing to systemic iron overload. Disclosures Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Ganz:Intrinsic LifeSciences: Consultancy, Equity Ownership. Nemeth:Intrinsic LifeSciences: Consultancy, Equity Ownership; Silarus Therapeutics: Consultancy, Equity Ownership; Keryx: Consultancy; Ionis Pharmaceuticals: Consultancy; La Jolla Pharma: Consultancy; Protagonist: Consultancy.

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Iron Chelation Efficiency of Deferasirox (Exjade®, ICL670) in Patients with Transfusional Hemosiderosis.

Blood ◽

10.1182/blood.v106.11.2690.2690 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2690-2690 ◽

Cited By ~ 9

Author(s):

J. Porter ◽

C. Borgna-Pignatti ◽

M. Baccarani ◽

A. Saviano ◽

S. Abish ◽

...

Keyword(s):

Binding Capacity ◽

Iron Concentration ◽

Iron Chelation ◽

Iron Chelator ◽

Tridentate Ligand ◽

Average Dose ◽

Iron Intake ◽

Liver Iron ◽

Molecular Weights ◽

Iron Excretion

Abstract Iron excretion can be calculated according to Angelucci et al (NEJM 2000). As applied to the novel oral iron chelator deferasirox (DSX), chelation efficiency can then be determined as the % iron excretion vs theoretical iron binding capacity of chelator dose: % efficiency = [iron excretion (mg/kg/day)/chelator dose (mg/kg/day)] x [374/56] x 2 x 100 (374 and 56 represent the molecular weights of DSX and iron; factor 2 accounts for the tridentate ligand). In a total of 325 patients with β-thalassemia (n=285) or rare anemias, such as MDS (n=13), DBA (n=14) or other anemias (n=13), included in the DSX Phase II and III Studies 0108 and 0107, liver iron concentration (LIC) was evaluated by liver biopsy at baseline and study end. All patients were treated with once-daily oral DSX 5, 10, 20 or 30 mg/kg according to baseline LIC (2–3, >3–7, >7–14 and >14 mg Fe/g dw, respectively). In these patients, the average dose during study was 22.8 ± 7.6 mg/kg. The average iron intake was 0.37 mg/kg/day and was similar between dose cohorts. Efficiency of daily DSX treatment (mean ± SD) Baseline LIC 2–3 >3–7 >7–14 >14 DSX, mg/kg 5 (n=9) 10 (n=49) 20 (n=81) 30 (n=186) Iron excretion (mg/kg/day) 0.14 ± 0.1 0.21 ± 0.1 0.39 ± 0.1 0.57 ± 0.2 Iron intake (mg/kg/day) 0.39 ± 0.1 0.37 ± 0.1 0.38 ± 0.1 0.36 ± 0.1 Ratio iron excretion/intake 0.33 ± 0.2 0.53 ± 0.4 1.09 ± 0.5 1.66 ± 0.8 Efficiency (%) 31.6 ± 26.4 27.5 ± 18.4 27.1 ± 10.3 27.3 ± 12.4 There were no differences in the chelation efficiency of DSX between the overall initial dose groups, and thus between different LIC categories at baseline, or between age and disease groups. Using the estimated efficiency of 27%, and the formula above, the approximate dose (mg) needed to achieve iron balance corresponds to an iron intake in mg Fe/kg/day divided by 0.02. For a patient receiving 0.2, 0.4 or 0.6 mg/kg Fe/day the doses of 10, 20 or 30 mg/kg, respectively, are estimated to achieve iron balance (eg for a 44 kg person receiving 4 units of blood/month a dose of 30 mg/kg would be required to achieve iron balance). Further analysis reveals that chelation efficiency does appear to increase somewhat with iron intake: in patients with <0.3 mg/kg/day Fe (average 0.23) the estimated efficiency is 22%, but becomes 34% in those with >0.5 mg/kg/day Fe (average 0.55). Applying different chelation efficiency estimates for low and high iron intake, 14 and 22 mg/kg/day DSX, respectively, would be required to chelate the transfused iron. In Study 0107, 230 patients were treated with deferoxamine (DFO) at an average daily dose of 45 mg/kg (5 days/week). Using the molecular weight of DFO (656) and a factor of 1 for a hexadentate ligand in the calculation, the overall chelation efficiency for DFO is 13% (10–17% in the lowest and highest iron intake categories, respectively). These calculations, based on the formula of Angelucci et al, correspond well to the overall observation in the DSX clinical studies, that iron balance or net negative iron balance is achieved by daily doses of 20–30 mg/kg in regularly transfused patients. The results also confirm that the estimated chelation efficiency of DSX is around twice that of DFO.

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Magnetic Ressonance Imaging (MRI) in the Evaluation of Iron Overload in Patients with Beta Thalassaemia. The Brazilian National Program Preliminary Results.

Blood ◽

10.1182/blood.v106.11.3825.3825 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3825-3825

Author(s):

Nelson Hamerschlak ◽

Laercio Rosemberg ◽

Alexandre Parma ◽

Fernanda F. Assir ◽

Frederico R. Moreira ◽

...

Keyword(s):

Iron Overload ◽

Ventricular Function ◽

Iron Content ◽

Chelation Therapy ◽

Iron Concentration ◽

Iron Chelation ◽

Inverse Correlation ◽

Liver Iron ◽

Liver Iron Content ◽

Cooperative Program

Abstract Magnetic Ressonance Imaging (MRI) using T2 star (T2*) tecnique appears to be a very useful method for monitoring iron overload and iron chelation therapy in thalassaemia. In Brazil, we have around 400 thalassaemic major patients all over the country. They were treated with hipertransfusion protocols and desferroxamine and/or deferiprone chelation. We developed a cooperative program with the Brazilian Thalassaemic Patients Association (ABRASTA) in order to developT2* tecnique in Brazil to submit brazilian patients to an annual iron overload monitoring process with MRI.. We performed the magnetic ressonance T2* using GE equipment (GE, Milwaukee USA), with validation to chemical estimation of iron in patients undergoing liver biopsy. Until now, 60 patients were scanned, median age=23,2 (12–54); gender: 18 male (30%) and 42 female (70%). The median ferritin levels were 2030 ng/ml (Q1=1466; Q3=3296). As other authors described before, there was a curvilinear inverse correlation between iron concentration by biopsy, liver T2*(r=0,92) and also there were a correlation with ferritin levels. We also correlated myocardial iron measured by T2* with ventricular function.. As miocardial iron increased, there was a progressive decline in ejection fraction and no significant correlation was found between miocardial T2* and the ferritin levels. Liver iron content can be predicted by ferritin levels. On the other hand, cardiac disfunction is the most important cause of mortality among thalassaemic patients. Since Miocardio iron content cannot be predicted from serum ferritin or liver iron, and ventricular function can only detect those with advance disease, intensification and combination of chelation therapy, guided by T2* MRI tecnique should reduce mortality from the reversible cardiomyopathy among thalassaemic patients.

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

Blood ◽

10.1182/blood.v112.11.439.439 ◽

2008 ◽

Vol 112 (11) ◽

pp. 439-439 ◽

Cited By ~ 1

Author(s):

Jong Wook Lee ◽

Sung-Soo Yoon ◽

Zhi Xiang Shen ◽

Hui-Chi Hsu ◽

Arnold Ganser ◽

...

Keyword(s):

Abdominal Pain ◽

Aplastic Anemia ◽

Iron Reduction ◽

Chelation Therapy ◽

Iron Concentration ◽

Iron Chelation ◽

Efficacy And Safety ◽

Iron Intake ◽

Liver Iron ◽

Transfusion Requirements

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

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

Blood ◽

10.1182/blood.v116.21.5168.5168 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5168-5168

Author(s):

Regine Grosse ◽

Gritta Janka ◽

Andrea Jarisch ◽

Peter Nielsen ◽

Jin Yamamura ◽

...

Keyword(s):

Side Effects ◽

Conflicts Of Interest ◽

Iron Concentration ◽

Iron Chelation ◽

Thalassemia Major ◽

Transfusion Rate ◽

Liver Iron Concentration ◽

Measurement Interval ◽

Liver Iron ◽

Rbc Transfusion

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

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RNAi-Mediated Inhibition of Tmprss6 Ameliorates Anemia and Secondary Iron Overload in a Mouse Model of β-Thalassemia Intermedia and Decreases Iron Overload in Hfe−/− Mice

Blood ◽

10.1182/blood.v120.21.1018.1018 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1018-1018

Author(s):

Paul J Schmidt ◽

Anoop K Sendamarai ◽

Ivanka Toudjarska ◽

Tim Racie ◽

Jim S Butler ◽

...

Keyword(s):

Mouse Model ◽

Iron Overload ◽

Iron Absorption ◽

Disease Phenotype ◽

Ineffective Erythropoiesis ◽

Employment Equity ◽

Liver Iron ◽

Secondary Iron Overload ◽

Equity Ownership ◽

Low Levels

Abstract Abstract 1018 β-Thalassemia intermedia (TI), an inherited hemoglobinopathy caused by partial loss of β-globin synthesis, is characterized by anemia, extramedullary hematopoiesis and ineffective erythropoiesis as well as secondary iron overload. Hereditary hemochromatosis (HH) is most frequently caused by mutations in HFE and is marked by excess uptake of dietary iron with concomitant tissue iron overload. In both diseases, increased iron absorption is due to inappropriately low levels of the liver hormone, hepcidin (encoded by Hamp1). The membrane serine protease Matriptase-2 (encoded by Tmprss6) attenuates BMP-mediated Hamp1 induction by cleaving the BMP co-receptor, hemojuvelin. Previously, it has been shown that elevating Hamp1 expression by genetic inactivation of Tmprss6 reduces disease severity in the Hbbth3/+ mouse model of TI and prevents iron overload in Hfe−/− mice. Therefore, a therapeutic approach comprising specific inhibition of Tmprss6 could prove efficacious in TI and HH. Here we show that systemic administration of a potent lipid nanoparticle (LNP) formulated siRNA directed against Tmprss6 leads to >80% inhibition of Tmprss6 mRNA in the livers of Hbbth3/+ and Hfe−/− mice with concomitant >2-fold elevation in Hamp1 expression. In the TI model, Tmprss6 silencing leads to ∼30% reductions in serum iron and non-heme liver iron. In Hfe−/− mice, serum iron and non-heme liver iron are similarly reduced, and Perls staining of peri-portal iron is diminished. Remarkably, the partial iron restriction induced by Tmprss6 inhibition in Hbbth3/+ mice leads to dramatic improvements in the hematological aspects of the disease phenotype: the severity of the anemia is decreased as evidenced by an approximately 1 g/dL increase in total hemoglobin and a 50% decrease in circulating erythropoietin levels. As in the human disease, Hbbth3/+ mice exhibit the hallmarks of ineffective erythropoiesis including splenomegaly, decreased erythrocyte survival and marked reticulocytosis. Treatment with LNP formulated Tmprss6 siRNA leads to a dramatic 2–3 fold decrease in spleen size, a 3–4 fold decrease in reticulocyte counts and a >7-day increase in RBC half-life. Histological analysis of spleens from Tmprss6 siRNA treated animals demonstrates restoration of normal splenic architecture, as well as a reduction in the number of Tfr1-positive erythrocyte precursors in the spleen. Furthermore, as evidenced by the near normalization of blood smears, the overall quality of erythropoiesis in treated animals is vastly improved. Taken together, these data demonstrate that RNAi-mediated silencing of liver Tmprss6 elevates Hamp1 expression and reduces iron overload in both TI and HH model mice. More significantly, Tmprss6 siRNA treatment ameliorates all aspects of the disease phenotype in the TI mouse model. These results support the development of an RNAi therapeutic targeting TMPRSS6 for the treatment of TI, HH and potentially other disorders characterized by excess iron absorption due to physiologically inappropriately low levels of hepcidin. Disclosures: Racie: Alnylam Pharmaceuticals: Employment. Butler:Alnylam Pharmaceuticals, Inc.: Employment, Equity Ownership. Bumcrot:Alnylam Pharmaceuticals, Inc.: Employment, Equity Ownership.

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