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  • 1
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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
    RVK:
    XA 33000
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 2
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    Genetic Heterogeneity of Alpha - and Beta - Globin Mutations in a German Multiethnic Population Group
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 5185-5185
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 5185-5185
    Abstract: Abstract 5185 Thalassemia syndromes are among the most common hereditary diseases worldwide and are widespread throughout the Mediterranean Region, Africa, the Middle East, India, Burma, the Southeast Asia and Indonesia. Similarly, hemoglobinopathies are common in different ethnic groups and mixed syndromes of Thalassemia and hemoglobinopathies exist. In this retrospective study we report the number and type of Thalassemia mutations and their combination with hemoglobinopathies detected mostly in individuals with a migration background now living in Germany. DNA samples were analyzed by polymerase chain reaction (PCR) and direct DNA-sequencing and additionally by multiplex ligation-dependent amplification (MRC-HOLLAND MLPA®). Mutations in one or both beta-globin chains were found in 77 patients. Most of these mutations were beta Thalassemia mutations, n=41 (Thalassemia minor n=33, Thalassemia major/intermedia n=7, homozygous Quin-Hai Hemoglobinopathy n=1). In 34 samples we found the hemoglobin S single base mutation c. 20A 〉 T p. E7V, either alone or in combination with a hemoglobin C mutation c. 19G 〉 A p. E7K or beta Thalassemia mutation (HbAS n=14, HbSS n=12, HbSC n=6, HbSThal n=2). In two patients we found only the hemoglobin C mutation by itself (HbAC n=1, HbCC n=1). In 52 samples we found mutations on the alpha-globin chains, most often the 3. 7KB deletion (n=27), followed by the SEA (n=4), the 20. 5 KB deletion (n=4), the 4. 2 KB deletion (n=4), the Dutch deletion (n=3) and alpha triplication (n=3). Two of the remaining seven samples showed new alpha Thalassemia mutations which have not been described yet. In an additional 34 DNA samples we found a combination of alpha- and beta-globin chain changes. In 4 of these samples we detected new mutations in the alpha-globin chains. The prevalence of mutations in the alpha- and beta-globin chains varies greatly because of a complex ethnic structure of our patients. Changes of the alpha-globin chains could not be safely detected by hemoglobin-electrophoresis. These situations are very important for genetic counseling in a population in which consanguineous marriages are common. Furthermore, alpha-globin mutations are genetic modifiers for beta Thalassemia and sickle cell disease and will influence the phenotype of beta-globin chain mutations. Patients with a compound heterozygous mutation for beta Thalassemia will probably not be detected by hemoglobin-electrophoresis alone, as in milder forms and early childhood the hemoglobin is not severely decreased and hemoglobin electrophoresis may be misinterpreted for Thalassemia minor. Our findings underline the heterogeneity of beta-globin and alpha-globin chain mutations and the importance of hematological and molecular analyses in the diagnosis and genetic counseling. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.5185.5185
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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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
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    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 6
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    A randomized, placebo-controlled, double-blind trial of canakinumab in children and young adults with sickle cell anemia
    American Society of Hematology ; 2022
    In:  Blood Vol. 139, No. 17 ( 2022-04-28), p. 2642-2652
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    In: Blood, American Society of Hematology, Vol. 139, No. 17 ( 2022-04-28), p. 2642-2652
    Abstract: Excessive intravascular release of lysed cellular contents from damaged red blood cells (RBCs) in patients with sickle cell anemia (SCA) can activate the inflammasome, a multiprotein oligomer promoting maturation and secretion of proinflammatory cytokines, including interleukin-1β (IL-1β). We hypothesized that IL-1β blockade by canakinumab in patients with SCA would reduce markers of inflammation and clinical disease activity. In this randomized, double-blind, multicenter phase 2a study, patients aged 8 to 20 years with SCA (HbSS or HbSβ0-thalassemia), history of acute pain episodes, and elevated high-sensitivity C-reactive protein & gt;1.0 mg/L at screening were randomized 1:1 to received 6 monthly treatments with 300 mg subcutaneous canakinumab or placebo. Measured outcomes at baseline and weeks 4, 8, 12, 16, 20, and 24 included electronic patient-reported outcomes, hospitalization rate, and adverse events (AEs) and serious AEs (SAEs). All but 1 of the 49 enrolled patients were receiving stable background hydroxyurea therapy. Although the primary objective (prespecified reduction of pain) was not met, compared with patients in the placebo arm, patients treated with canakinumab had reductions in markers of inflammation, occurrence of SCA-related AEs and SAEs, and number and duration of hospitalizations as well as trends for improvement in pain intensity, fatigue, and absences from school or work. Post hoc analysis revealed treatment effects on weight, restricted to pediatric patients. Canakinumab was well tolerated with no treatment-related SAEs and no new safety signal. These findings demonstrate that the inflammation associated with SCA can be reduced by selective IL-1β blockade by canakinumab with potential for therapeutic benefits. This trial was registered at www.clinicaltrials.gov as #NCT02961218.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.2021013674
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
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  • 7
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    Analysis of a cohort of 101 CDAII patients: description of 24 new molecular variants and genotype‐phenotype correlations
    Wiley ; 2016
    In:  British Journal of Haematology Vol. 175, No. 4 ( 2016-11), p. 696-704
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    In: British Journal of Haematology, Wiley, Vol. 175, No. 4 ( 2016-11), p. 696-704
    Abstract: Congenital dyserythropoietic anaemia type II ( CDAII ) is a rare autosomal recessive disease characterized by ineffective erythropoiesis, haemolysis, erythroblast morphological abnormalities, hypoglycosylation of some red blood cell membrane proteins, particularly band 3, and mutations in the SEC 23B gene. We report the analysis of 101 patients from 91 families with a median follow‐up of 23 years (range 0–65); 68 patients are newly reported. Clinical and haematological parameters were separately analysed in early infancy and thereafter, when feasible. Molecular analysis of the SEC 23B gene confirmed the high heterogeneity of the defect, leading to the identification of 54 different mutations, 24 of which are newly described. To evaluate the genotype‐phenotype correlation, patients were grouped according to their genotype (two missense mutations vs. one missense/one drastic mutation) and assigned to two different severity gradings based on laboratory data and on therapeutic needs; by this approach only a weak genotype‐phenotype correlation was observed in the analysed groups.
    Type of Medium: Online Resource
    ISSN: 0007-1048 , 1365-2141
    URL: Issue
    URL: Article
    DOI: 10.1111/bjh.2016.175.issue-4
    DOI: 10.1111/bjh.14271
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    Language: English
    Publisher: Wiley
    Publication Date: 2016
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  • 8
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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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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 9
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    Newborn screening for sickle cell disease
    Springer Science and Business Media LLC ; 2021
    In:  Monatsschrift Kinderheilkunde
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    In: Monatsschrift Kinderheilkunde, Springer Science and Business Media LLC
    Type of Medium: Online Resource
    ISSN: 0026-9298 , 1433-0474
    URL: Article
    DOI: 10.1007/s00112-021-01213-w
    RVK:
    XA 10000
    Language: German
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 1462918-5
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  • 10
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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
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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