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  • 1
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    Serum ferritin is not a reliable predictor to determine iron overload in thalassemia major patients post‐hematopoietic stem cell transplantation
    Wiley ; 2018
    In:  European Journal of Haematology Vol. 101, No. 6 ( 2018-12), p. 791-797
    Details
    In: European Journal of Haematology, Wiley, Vol. 101, No. 6 ( 2018-12), p. 791-797
    Abstract: Iron overload (IO) in transfusion‐dependent anemia persists after hematopoietic stem cell transplantation (HSCT) and can cause long‐term organ damage. In many studies, the diagnosis of IO before and after HSCT is based on serum ferritin (SF) levels rather than on assessment of liver iron concentration (LIC) by MRI or SQUID. Method In a retrospective multicenter study, we analyzed the concordance for indication of iron depletion therapy and correlation between LIC and SF of 36 thalassemia patients after HSCT. LIC was determined either by MRI‐R2 (FerriScan®) or SQUID. Results The concordance between LIC and SF varies over time after transplant ( P  = 0.011). The correlation between SF and LIC was strong in the first year (Spearman's rho 0.75; P   〈  0.001). In agreement, the concordance between SF and LIC concerning indication for treatment was close to 1 with an overall error rate ca. of 10%. In particular in the first year after HSCT, SF underestimates the degree of iron overload. However, in the longitudinal analysis since the second year post‐HSCT onward no association was found between LIC and SF ( P  = 0.217). Furthermore, in the second year after HSCT, the overall error rate was 35%, whereas in the 3rd, 4th, and 〉 4th year, it was 58%, 60%, and 25%, respectively. Conclusions Our data suggest serum ferritin is not a reliable predictor to determine iron overload in thalassemia patients after HSCT.
    Type of Medium: Online Resource
    ISSN: 0902-4441 , 1600-0609
    URL: Issue
    URL: Article
    DOI: 10.1111/ejh.2018.101.issue-6
    DOI: 10.1111/ejh.13169
    Language: English
    Publisher: Wiley
    Publication Date: 2018
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  • 2
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    Safe and Efficient Chelation by Deferasirox In Thalassemia Major Patients with Low Liver and Cardiac Iron Concentrations
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 5168-5168
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 5168-5168
    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.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.5168.5168
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    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 3
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    Iron Stores in Patients with Myelodysplasia and Aplastic Anemia.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 3726-3726
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 3726-3726
    Abstract: Patients with myelodysplastic syndromes (MDS), osteomyelofibrosis (OMF), or severe aplastic anemia (SAA) suffer from ineffective erythropoiesis due to pancytopenia, which is treated with red blood cell transfusion leading to iron overload. Especially in low-risk patients with mean survival times of 〉 5 years, potentially toxic levels of liver iron concentration (LIC) can be reached. We hypothesize that the higher morbidity seen in transfused patients may be influenced by iron toxicity. Following a meeting in Nagasaki 2005, a consensus statement on iron overload in myelodysplastic syndromes has been published, however, there is still no common agreement about the initiation of chelation treatment in MDS patients. In the present study, a total of 67 transfused patients with MDS (n = 20, age: 17 – 75 y), OMF (n = 4, age: 48 – 68 y), SAA (n = 43, age: 5 – 64 y) were measured by SQUID biomagnetic liver susceptometry (BLS) and their liver and spleen volumes were scanned by ultrasound at the Hamburg biosusceptometer. Less than 50 % were treated with DFO. LIC (μg/g-liver wet weight, conversion factor of about 6 for μg/g-dry weight) and volume data were retrospectively analyzed in comparison to ferritin values. Additionally, 15 patients (age: 8 – 55 y) between 1 and 78 months after hematopoietic cell transplantation (HCT) were measured and analyzed. LIC values ranged from 149 to 8404 with a median value of 2705 μg/g-liver, while serum ferritin (SF) concentrations were between 500 and 10396 μg/l with a median ratio of SF/LIC = 0.9 [(μg/l)/(μg/g-liver)] (range: 0.4 to 5.2). The Spearman rank correlation between SF and LIC was found to be highly significant (RS = 0.80, p 〈 0.0001), however, prediction by the linear regression LIC = (0.83± 0.08)·SF was poor (R2 = 0.5) as found also in other iron overload diseases. Although iron toxicity is a long-term risk factor, progression of hepatic fibrosis has been observed for LIC 〉 16 mg/g dry weight or 2667 μg/g-liver (Angelucci et al. Blood2002; 100:17–21) within 60 months and significant cardiac iron levels have been observed for LIC 〉 350 μmol/g or 3258 μg/g-liver (Jensen et al. Blood2003; 101:4632-9). The Angelucci threshold of hepatic fibrosis progression was exceeded by 51 % of our patients, while 39 % were exceeding the Jensen threshold of potential risk of cardiac iron toxicity. The total body iron burden is even higher as more than 50 % of the patients had hepatomegaly (median liver enlargement factor 1.2 of normal). A liver iron concentration of about 3000 μg/g-liver or 18 mg/g-dry weight has to be seen as latest intervention threshold for chelation treatment as MDS patients are affected by more than one risk factor. A more secure intervention threshold would be a LIC of 1000 μg/g-liver or 4 – 6 mg/g-dry weight, corresponding with a ferritin level of 900 μg/l for transfused MDS patients. Such a LIC value is not exceeded by most subjects with heterozygous HFE-associated hemochromatosis and is well tolerated without treatment during life-time. Non-invasive liver iron quantification offers a more reliable information on the individual range of iron loading in MDS which is also important for a more rational indication for a chelation treatment in a given patient.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.3726.3726
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
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  • 4
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    Iron Trafficking and Distribution in Transfusional Overload: Insights From Comparing Diamond Blackfan Anemia with Sickle Cell Disease and Thalassemia
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 995-995
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 995-995
    Abstract: Abstract 995 Background: β-thalassemia major (TM) is the paradigm for chronic transfusional iron overload, in which the extra-hepatic organ failure is best described. In Sickle Cell Disease (SCD), these consequences appear later and at a lower frequency. In chronically transfused Diamond Blackfan Anemia (DBA), extra-hepatic iron overload, although less well documented, appears to occur early and at high frequency. A Multicenter Study of Iron Overload (MCSIO) aims to explore how key candidate factors affect iron distribution; including inflammation, ineffective erythropoiesis, level of iron overload, and hepcidin synthesis. Plasma non-transferrin bound iron (NTBI) could be a key mechanism by which iron is delivered to tissues and may determine the propensity for extra-hepatic iron distribution. Here we focus on how markers of ineffective erythropoiesis (IE) and erythron expansion impact iron distribution, with particular reference to NTBI and iron distribution determined by MRI. Methods: Iron-overloaded patients (5 TM, 5 SCD, and 5 DBA) with ferritin 〉 1500 g/dl or LIC 〉 7 mg/g dry wt, age ≥16, age 0 to 9 at initiation of transfusion and 10 to 20 years of transfusion exposure were enrolled from 3 sites in the US and Europe. 5 non-transfused healthy controls were also enrolled. A detailed medical, transfusion and chelation history were obtained with standardized MRI evaluations for hepatic, cardiac, and pituitary iron deposition. Fasting, early morning blood samples were obtained one day prior to transfusion. Chelation was held for 72 hours prior to each sample. Results: Results are shown in the table as median values. DBA patients had the highest NTBI prior to transfusion despite having the lowest ferritin and LIC levels. GDF15 levels were highest in TM, with similar levels in SCD and DBA. EPO levels were nearly two orders of magnitude higher in DBA than TM or SCD. DBA patients also had the highest median cardiac R2*; two patients showing values above the control range. Whereas the median pituitary R2 in DBA was not above control, two of the patients had the highest R2 values, suggesting heavy iron deposition. EPO values in DBA are nearly two orders of magnitude higher that in SCD or TM despite similar pre-transfusion Hb values. GDF15 values are approximately three times controls, while soluble transferrin receptors (sTfR) values are almost undetectable. With SCD, no patients had increased cardiac iron loading, despite median SF and LIC being the highest in this group. Surprisingly all SCD patients had pituitary R2 values above the upper limit of normal. 1 TM patient had increased cardiac R2* whereas three had increased pituitary iron. In TM, NTBI was strongly correlated with GDF15 (Pearson's Rho=0.93) but in DBA, GDF15 was inversely correlated with NTBI (-.95). Conclusions: High GDF15 levels have been reported in conditions associated with IE, such as TM, but not in DBA. GDF15 reputedly suppresses hepcidin synthesis, thereby increasing iron absorption and potentially NTBI levels. The increased GDF15 in DBA, while sTfr remain less than controls, suggests that erythropoietic precursors do not reach the stage where sTfr are expressed and that this occurs at a later differentiation stage than GDF15. Increasing NTBI in TM with increasing GDF15 is consistent with IE contributing to NTBI formation, but the lack of this relationship in DBA suggest another mechanism for high NTBI. As the erythron is destroyed at a pre-hemoglobinised stage in DBA, IE would not contribute directly to NTBI formation. However, the extremely high EPO levels in DBA may inhibit hepcidin synthesis, as in other conditions, thereby increasing NTBI. This in turn may account for the extra-hepatic iron distribution demonstrated by MRI in DBA. The increased pituitary iron without cardiac loading in the heavily loaded SCD patients suggests that with prolonged exposure to heavy iron overload, the pituitary iron loading may be the first indicator of extra-hepatic deposition. Disclosures: Porter: Novartis: Consultancy, Research Funding. Walter:Novartis: Research Funding. Harmatz:Novartis: Research Funding; Ferrokin: Research Funding. Wood:Ferrokin Biosciences: Consultancy; Shire: Consultancy; Apotex: Consultancy, Honoraria; Novartis: Honoraria, Research Funding. Vichinsky:Novartis: Consultancy, Research Funding; ApoPharma: Consultancy, Research Funding; ARUP Research lab: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.995.995
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 5
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    Treatment of Iron Overload in Transfusion-Dependent Anemias Post Hematopoietic Stem Cell Transplantation: When to Start? When to Stop?
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 3369-3369
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 3369-3369
    Abstract: Introduction Iron overload (IO) in transfusion-dependent anemias (Thalassemia major, Sickle Cell Disease, Diamond-Blackfan and Fanconi Anemia) persist after hematopoietic stem cell transplantation (HSCT) and can result in increased morbidity in long term survivors, e.g. nonspecific liver dysfunction, hepatic cell carcinoma, heart failure and endocrinological complications. To reduce IO, phlebotomy or iron chelation is a required and effective treatment. Although existing recommendations for screening and prevention of late effects following HSCT suggest determining serum ferritin (SF) levels 1year post transplant, there are no clear guidelines for screening IO and initiating treatment. It is well known that SF levels depend on several factors beyond IO, e.g. infection or graft versus host disease, thus it is very often elevated as an acute phase protein in the post-transplant period. Aim of the Study In a multicenter, retrospective study we analyzed the concordance between liver iron concentration (LIC) and SF in 90 measurements of 33 patients (median age 8.9 y, range 1-11 y) with transfusion-dependent anemias (Thalassemia major, Diamond-Blackfan and Fanconi Anemia) who underwent HSCT between 1996 and 2014. LIC was determined either by MRI-R2 (Ferriscan®) or SQUID liver susceptometry. Statistical methods We examine the concordance between the classification according to LIC and SF: for SF 〈 800 μg/L, SF 〉 800 μg/L, and for the total range of SF levels. Pearson correlation was used to examine the relationship between paired values of LIC and SF. To analyze the classification sensitivity of SF levels according to LIC ≥ 4.5 mg/gdw we applied receiver operating characteristic (ROC) analysis. This approach estimates the sensitivity and the specificity as function of each SF cut-off level. The predictive accuracy of SF measurements in predicting LIC classification was investigated by area under the ROC curve. All statistical tests are two-sided with a significance level of 5%. Data analysis was performed using commercial software (R, ROCR package and Graph Prism software) Results Correlation between serum ferritin and LIC A moderate correlation among ferritin and LIC was found for the overall measurements (n=90). The Pearson coefficient correlation was equal to 0.69 (p 〈 0.001), with 95% confidence interval [0.57 - 0.79]. When we analyzed the correlation between ferritin and LIC only for measurements with SF 〈 800 μg/L (n=25) the correlation coefficient is equal to 0.26. For this group, a very weak association among LIC and SF was found (p=0.2). In the group with SF 〉 800 μg/L (n=65) the relationship is moderate (p 〈 0.001), with a Pearson correlation coefficient equal to 0.585 (Fig. 1). Concordance of the classification according serum ferritin and LIC In labor analysis and scans via MRI and SQUID technique the paired values of 90 LIC and SF were assessed. In accordance to the LIC threshold ≥4.5 mg/gdw 74 measurements demonstrated a demand of therapy. A total of 16 measurements did not indicate any requirement of therapy. A total of 65 measurements had SF ≥ 800 μg/L and 25 measurements had SF 〈 800 µg/l, indicated therapy onset and no therapy, respectively. The false positive rate was 22% (16/74) and the false negative rate was 44% (7/16). The overall error was 26% (23/90). The predictive accuracy of SF to predict classification of LIC for the whole measurements was 77.5%. The accuracy for the measurements 〉 800 μg/L (n=65) was 81%. Instead, ROC analysis for SF measurements 〈 800 μg/L (n=25) indicates non-informative prediction (area=0.53) (Fig. 2). Conclusion The values of of SF 〉 800 μg/L are applicable for predicting the classification according to LIC at a threshold ≥ 4.5 mg/gdw. A SF 〈 800 μg/L is not appropriate for predicting an initiating treatment of IO, because of a weak correlation (p=0.2) between paired SF and LIC values. Furthermore, the accuracy of SF indicated a non-informative prediction of classification according to LIC (ROC area = 0.53). Our data suggest that initiating and stopping treatment of IO in transfusion dependent patients after HSCT should be done on the basis of LIC measured via MRI or SQUID instead of SF measurements only. Figure 1. Correlation among LIC and SF Figure 1. Correlation among LIC and SF Figure 2. Accuracy of SF to predict LIC (ROC curve) Figure 2. Accuracy of SF to predict LIC (ROC curve) Disclosures Grosse: Swedish Orphan Biovitrum: Honoraria; Novartis Oncology: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.3369.3369
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 6
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    Measurement of Liver Iron Concentration by Quantum Interference Device Biosusceptometry (SQUID) Validates Serum Ferritin As Prognostic Parameter for Allogeneic Stem Cell Transplantation
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 1018-1018
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    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1018-1018
    Abstract: Abstract 1018 Introduction: There is conflicting data regarding the role of serum ferritin (SF) as an independent prognostic factor for outcome after allogeneic stem cell transplantation (allo-SCT). SF is a surrogate parameter for iron overload and - as an acute phase-protein - can be confounded by many factors. An independent, non-invasive measurement of iron overload is needed. Determining iron content through SQUID correlates well with results of liver biopsies (Nielsen et al. 1998). This method measures the interference of an exteriorly applied small but highly constant magnetic field by the paramagnetic liver storage iron of the patient. Methods: We conducted a single-center retrospective analysis from October 1994 to December 2012, comparing the effect of SF and liver iron content measured by SQUID shortly before transplantation on overall survival (OS), event-free survival (EFS) and transplant-related mortality (TRM) in 143 patients (median age 40 years) undergoing allo-SCT (73% reduced intensity regimen). The diagnoses were subdivided into 4 groups: myelodysplastic syndrome, secondary acute myeloid leukemia (AML), primary myelofibrosis, primary AML and other. Statistical calculations employed Pearson's correlation, ordinal logistic regression, Cox regression analysis and multiple Cox regression analyses with backward elimination. Results: Correlation between SF and SQUID showed a highly significant result of r=0.5 (p 〈 0.001). The chance of infection was increased 2.4-fold (CI 1.22,4.71) when SQUID values ranged 〉 1000 μg Fe/g liver. We found similar results for SF 〉 1000 ng/ml (p 0.003), where the risk of infection was increased 2.87–fold (CI 1.43;5.78). A significant association between SQUID und fungal infection was also seen (p 0.004). For patients with SQUID 〉 1000 the chance of proven fungal infection versus fungal infection of all other categories was increased 3.08-fold (CI 1.43,6.63). Similarly an association between SF 〉 1000 and fungal infection could be demonstrated (p 0.001), with a 4.04-fold increased chance of proven fungal infection versus lower fungus categories for patients with SF values 〉 1000. There was no association between continuous SQUID-, respectively SF values and VOD (veno-occlusive disease) or acute GvHD. The following variables were significantly related with OS: chronic GvHD (HR 0.326, CI 0.13–0.83, p 0.019,), sepsis (p 0.002, HR 2.94 CI 1.48–5.83), new onset cardiac abnormalities (p 0.001, HR 3.21, CI 1.64–6.27), SF 〉 1000 (p 0.033, HR 2.09, CI 1.06–4.11). For EFS we found statistically significant results for chronic GvHD (p 0.040, HR 0.45, CI 0.21–0.97), sepsis (p 0.012, HR 2.35, CI 1.21–4.58), cardiac abnormalities (p 0.001, HR 2.81, CI 1.50–5.29), SF 〉 1000 (p 0.016, HR 2.15, CI 1.15–4.10) and time to engraftment (p 0.038, HR 0.934, CI 0.89–1.00). For TRM, statistically significant results were found for sepsis (p 0.005, HR 3.23, CI 1.43–7.29), cardiac abnormalities (p 〈 0.001, HR 5.21, CI 2.41–11.27), and age (p 0.034, HR 1.04, CI 1.00–1.08). Fungal infection of all categories was not statistically significant (p=1,101), but proven fungal infection in comparison with no fungal infection was found significant (p 0.018, HR 3.12, CI 1.22–7.99. In the multivariate analysis SF and SQUID (categorical and continuous) were not significant factors for OS, EFS or TRM. Conclusion: Our data confirmed previous publications that SF 〉 1000 increases the risk of infection, moreover fungal infection. In the univariate analysis it is significantly associated with OS and EFS during allo-SCT. As SQUID values correlate well with SF, we could show that SF is indeed a good surrogate parameter for iron overload when measured shortly before allo-SCT. We are now in need of prospective trials investigating the effect of iron chelation before or during allo-SCT on transplant outcome. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.1018.1018
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    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 7
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    Distribution of cardiac iron measured by magnetic resonance imaging (MRI)-R*2
    Wiley ; 2010
    In:  Journal of Magnetic Resonance Imaging Vol. 32, No. 5 ( 2010-11), p. 1104-1109
    Details
    In: Journal of Magnetic Resonance Imaging, Wiley, Vol. 32, No. 5 ( 2010-11), p. 1104-1109
    Type of Medium: Online Resource
    ISSN: 1053-1807
    URL: Article
    DOI: 10.1002/jmri.22364
    Language: English
    Publisher: Wiley
    Publication Date: 2010
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  • 8
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    Optimizing Iron Chelator Treatment in Cardiac and Hepatic Siderosis: Efficacy of Divided Deferasirox (EXJADER) – Doses
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 2110-2110
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2110-2110
    Abstract: Abstract 2110 Introduction: Iron chelation is the life-saving therapy in patients with chronic transfusion therapy. Treatment with deferoxamine, deferiprone or deferasirox has dramatically improved the life expectancy, but still myocardial siderosis and hepatic siderosis is cause of morbidity and mortality in regularly transfused patients with ß-thalassemia major (TM) or Diamond-Blackfan Anemia (DBA). Deferasirox (DSX) a once-daily oral iron chelator has demonstrated efficacy in reducing hepatic iron and body iron burden, as well as cardiac iron. But in patients with severe cardiac siderosis (T2* ≤ 10ms) a combination therapy with deferiprone (Ferriprox®) and deferoxamine (Desferal®) is the recommended therapy. However, some patients will not benefit from this treatment due to unacceptable toxicity, poor response or noncompliance. Method: We tested a twice-daily deferasirox (Exjade®) -dose with special respect to its efficacy on reducing cardiac iron overload. A group of six patients with severe secondary siderosis was studied, TM (n=5) and DBA (n=1), (5 females, age 8–37 years, mean age 27.7 years). In all patients the liver iron concentration was measured repeatedly by SQUID biosusceptometry or by magnetic resonance imaging (MRI) using the MRI-R2 technique (St. Pierre et al, 2005). In 4 patients with severe cardiac siderosis (T2* ≤ 10ms) we also followed the cardiac iron concentration by MRI using a single breath-hold, multi-echo T2* method. Patients received a daily DSX dose of 19 mg/kg/d – 45 mg/kg/d, with a mean dose of 32 mg/kg/d. Results: The mean initial liver iron concentration of 2.7 mg/g-liver (0.96 – 5.5mg/g) decreased to 1.5 mg/g-liver (0.6 – 3.9 mg/g). The mean monthly liver iron clearance was 6.8%/month (1.7 – 16.8%/month) in a treatment interval of 4 – 26 months (mean: 9.8 months), the patients demonstrated a significant liver iron reduction of 44.4%. The mean serum ferritin was reduced from 3048 μg/l to 1786 μg/l. The mean monthly cardiac iron clearance was 3.1%/month (1.2 – 4.7%/month) and the mean T2* value improved from 9.5 ms to 14.3 ms (+50%). We showed a substantial improvement in patients with severe cardiac siderosis with a T2* improvement of 50 % after a mean treatment period of 12 months with a mean DSX dose of 32 mg/kg/d. In comparison, an improvement of 23.8% was found in 6 patients with T2* 〈 10 ms, after a treatment period of 18 months with a once daily DSX mean dose of 38 mg/kg/d (Pathare et al, 2010). Other authors reported an improvement of 10.8% in 47 patients (T2* 〈 10 ms, treatment period 12 months) with a once daily DSX mean dose of 32 mg/kg/d (Pennell et al, 2009). No severe side effects were seen in our patients and only minor increases in creatinine values, which were reversible with dose reduction. Conclusion: Deferasirox divided in twice daily doses is a safe and effective therapy for patients with severe cardiac iron overload (T2* 〈 10ms) or hepatic iron overload, who do not well tolerate a combination therapy with deferiprone and deferoxamine. Disclosures: Off Label Use: Deferasirox (Exade)is given instead of a once daily dose, in a twice daily divided dose. The daily dose of Deferasirox is in recommended range.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.2110.2110
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 9
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    Bone Marrow Iron Assessment By MRI-R2* and Its Relation to Deferasirox Treatment in Patients with Iron Overload
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 3358-3358
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    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 3358-3358
    Abstract: Objective: Patients with iron overload suffer from different organ damage due to increased iron concentration. Iron overload in the bone marrow and the influence of iron chelation therapy on bone marrow iron content may play an additional role in these patients and is until now not well examined. Material and Methods: We performed MRI-R2* measurements in the vertebral bone marrow using water-fat chemical shift relaxometry for estimation of iron and fat content in comparison to hepatic and splenic iron concentrations and serum ferritin in patients with iron overload due to hereditary hemochromatosis (HHC) and patients with siderosis due to red blood cell transfusions and /or iron loading anemia. 112 patients with iron overload, mean age: 32 y (transfusion dependent thalassemia major (TM) n=65, Diamond-Blackfan anemia (DBA) n=12, HHC n=10, iron loading anemia (EA) n=7, transfusion siderosis n=12 and stem cell transplantation n=6) and 14 control subjects underwent MRI for determination of the transverse relaxation rate R2*assessed from ROI based signal intensities of one transversal slice (10mm) through the liver, spleen, and mid-vertebral bone marrow. Breathhold water-fat relaxometry (12 echo times, TE=1.3-26ms, FA=20°, bandwidth=1955Hz/px) was performed to determine apparent fat contents (aFC) and bone marrow R2*. Additionally, serum ferritin values were assessed. In 67 patients with TM under chelation therapy with Deferasirox (DFX) we compared R2* bone marrow iron content with the ratio of the chelator dose rate (Deferasirox, [mmol/d]) to the total liver iron (LivFe = LIC*volume [g-Fe] ). Results: Relative to controls (n=14, R2* = 95s-1) and HHC (n=10, R2* = 95s-1), median bone marrow R2* rates were significantly increased in patients with TM (n=65, R2* = 398s-1, p 〈 10-4) or DBA (n=12, R2* = 252s-1, p = 0.005). R2* of the bone marrow significantly correlated with serum ferritin (rS=0.52, p 〈 10-4), splenic R2* (rS=0.43, p 〈 10-4), cardiac R2* (rS=0.43, p 〈 10-4), and hepatic R2* (rS=0.37, p 〈 10-4). No significant correlation of aFC with marrow R2* could be obtained. The bone marrow iron content was higher in patients with a low Deferasirox (DFX) dose. A DFX dose 〉 150 (mmol/d)/g-Fe was a negativ predictor for increased bone marrow iron content (R2* 〉 700 1/s), but a significant correlation couldn't be found (r = 0,077), probably due to the low number of patients. The efficacy dose of DFX for a low bone marrow iron content seems to lay between a dose of 1mmol/d (18mg/d) and 2,5 mmol/d (45mg/d). A DFX dose 〉 2,5 mmol/d didn't seem to increase the efficacy. Table 1. Diagnosis (n) Age Median (IQR) KM R2* [s-1 ] Median (IQR) KM R2* 95 % range Control group (14) 29.8 (26.0) 95 (43) 62 - 134 TM ( 65) 30.6 (16.2) 398 (455) 73 - 1213 HH (10) 56.4 (9.3) 95 (40) 61 - 270 EA (7) 46.6 (24.8) 191 (93) 159 - 490 DBA (12) 27,6 (14.6) 252 (250) 62 - 652 TS(12) 32.3 (46.2) 322 (304) 116 - 607 BMT (6) 20 (20.8) 285 (342) 105 - 470 Conclusion: Water-fat chemical shift relaxometry allows precise determination of bone marrow R2* rates and estimation of the apparent fat content, which may add additional information to these patients. Patients with transfusion related iron overload have significant higher bone marrow iron content than patients with iron overload due to hereditary hemochromatosis. DFX in an adäquat dose seem to prefent bone marrow iron overload. Disclosures Grosse: Swedish Orphan Biovitrum: Honoraria; Novartis Oncology: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.3358.3358
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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    detail.hit.zdb_id: 80069-7
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  • 10
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    Bone Microarchitecture Parameter for Early Diagnosis of Osteopenia in Thalassemia.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 2772-2772
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 2772-2772
    Abstract: In recent decades, survival in thalassemia patients has been prolonged; as a result, complications such as osteoporosis not previously observed will need earlier attention and better diagnostic tools. The diagnosis of osteoporosis is typically made by endocrine assessment and bone mineral density (BMD) measurements like dual energy x-ray absorptiometry (DXA). However, DXA may be insufficient to assess fracture risk in patients with thalassemia. We compared the microarchitecture and volumetric density of bone using high-resolution peripheral quantitative computed tomography (HR-pQCT) with planar BMD (DXA). In 18 transfused patients (age: 13 – 43 y) with beta-thalassemia, BMD of the lumbar spine (LS) and total hip was measured by DXA resulting in 7/18 patients with calculated Z-scores 〈 −2.0. In addition, we assessed the volumetric BMD and the bone microarchitecture of the non-dominant distal radius and tibia by HR-pQCT (XtremeCT®). BMD values by DXA, correlated with cortical thickness (Spearman rank correlation RS = 0.78, p=0.0001), cortical density (RS = 0.67, p=0.003), while LS Z-scores correlated best with total volumetric density (RS = 0.60, p=0.009) measured by HR-pQCT at the distal radius. Thus, a porous inner bone structure may appear masked by DXA measurements due to a massive corticalis. From the many different HR-pQCT parameters measured, those with the highest variability (COV) might be of greatest promise to predict defective bone architecture in thalassemia. These parameters were compared with reference data from Boutroy et al (J Clin Endocrinol Metab2005;90:6508–15) of normal and osteopenic women. Despite relative uniformity in DXA Z-scores, TbSp and TbSp SD parameters of the radius covered a broad range (COV, F-test) of high values in thalassemia compared to osteopenic women (Table I). The SD of the trabecular separation (TbSp SD) of radius and tibia, characterizing the porosity of the spongiosa, may become the most interesting parameter in thalassemia as it was significantly correlated with hip Z-score (RS = −0.49, p=0.044), osteocalcin (RS = −0.70, p=0.001), FSH (RS = −0.65, p=0.005) and with liver iron concentration (tibia: RS = 0.55, p=0.017), respectively. Patients with hypogonadism (n = 9/18) were significantly different (U-test) from normals with respect to TbSp (p=0.024) and TbSp SD (p=0.019), but not DXA Z-scores. Patients with fractures (n=5) had lower trabecular TbSp SD (p=0.02) at the tibia. For patients with hypogonadism, the measurement of bone microarchitecture by HR-pQCT of low radiation burden (3 μSv) may help to identify risk early and avoid or minimize future morbidity, especially, in the presence of still normal results from DXA measurements. Table I. Comparison of Z-scores and radial trabecular density (Dtrab), separation (TbSp), inhomogeneity (TbSp SD) with reference parameters from Boutroy et al (2005) of normal and osteopenic women (Fcritical 〉 3.0 for p 〈 0.001). Thalassemia (n = 18) Normal (n = 108) Osteopenic (n = 113) Parameter Mean ± SD COV Mean ± SD F-test Mean ± SD F-test LS-Zscore (DXA) −1.7 ± 1.3 80 % 0 NA −1.4 ± 0.6 4.9 Hip-Zscore (DXA) −1.3 ± 1.0 78 % 0 NA −1.6 ± 0.5 3.9 Dtrab [mg/cm3] 138 ± 71 51 % 160 ± 33 4.6 123 ± 36 3.9 TbSp [μm] 959 ± 1265 132 % 517 ± 88 207 656 ± 187 46 TbSp SD [μm] 600 ± 890 148 % 212 ± 58 236 342 ± 201 20
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.2772.2772
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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