Retrospective Evaluation of Patients Referred for Hemochromatosis Genetic Testing

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4035-4035
Author(s):  
Matthew B. Lanktree ◽  
Bruce B. Lanktree ◽  
John S. Waye ◽  
Guillaume Pare ◽  
Bekim Sadikovic ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Iron Overload ◽  
Board Of Directors ◽  
Transferrin Saturation ◽  
Organ Damage ◽  
Hfe Gene ◽  
Advisory Committees ◽  
Available N ◽  
Current Test ◽  
C282y Homozygote

Abstract Background: The common genetic test for hemochromatosis involves the genotyping of two polymorphisms in the HFE gene (C282Y and H63D). Current guidelines suggest testing of patients with ferritin greater than 300 µg/L and transferrin saturation greater than 45%. Testing of first degree relatives of confirmed HFE positive cases is also endorsed. However, the current test has poor sensitivity and specificity for iron overload causing end organ damage. We sought to evaluate biochemical parameters of patients referred for HFEtesting and identify those who received phlebotomy. Methods: After receiving ethics approval, electronic charts of patients referred to Hamilton Health Sciences, Hamilton, Ontario, Canada for HFE genetic testing between January 1, 2012 and December 31, 2012 were reviewed. Results: HFE genetic testing in 642 patients yielded 100 (15.6%) positive C282Y homozygote or C282Y/H63D compound heterozygote results. In patients with biochemical markers of iron overload available (n=160), patients with a risk HFE genotype had significantly higher iron saturation, serum iron, and hemoglobin (P<0.001), but did not have higher ferritin or liver enzymes. Only fifty percent of patients referred had biochemical evidence of iron overload (transferrin saturation [TS] > 45% and ferritin > 300). Of patients who required phlebotomy, only 27 of 40 (67.5%) were HFEpositive. Conclusion: Many factors affect the decision to phlebotomize a patient with suspected iron overload. However, it appears that most of the current HFE genetic testing being performed did not alter patient management. Disclosures Crowther: Asahi Kasai: Membership on an entity's Board of Directors or advisory committees; Bayer: Speakers Bureau; Celgene: Speakers Bureau; Shire: Speakers Bureau; Boehriniger Ingelheim: Consultancy; CSL Behring: Speakers Bureau; Leo Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Membership on an entity's Board of Directors or advisory committees; Viropharma: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Altered Iron Parameters and Hepcidin Levels in a General Population: Lessons from the CHRIS Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2239-2239
Author(s):  
Fabiana Busti ◽  
Annalisa Castagna ◽  
Giacomo Marchi ◽  
Oliviero Olivieri ◽  
Peter Pramstaller ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Iron Status ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
Organ Damage ◽  
Hfe Gene ◽  
Sequencing Data ◽  
Advisory Committees ◽  
South Tyrol ◽  
Iron Parameters

Introduction Environmental and genetic factors may lead to iron accumulation, causing irreversible organ damage. Homozygosity for the C282Y (C282Y +/+) and compound heterozygosity for the C282Y and H63D (C282Y-H63D) mutations of the HFE gene are associated with susceptibility to iron overload (IO). However, their clinical and biochemical expression is heterogeneous, with some patients showing only an increase of transferrin saturation (TSAT) for life, and others developing severe liver disease at a young age. Rarely, IO occurs in subjects without HFE-mutations or other acquired factors (e.g. alcohol intake, hemolysis, etc.). In these cases, non-HFE hemochromatosis is suspected, but the diagnosis is challenging, based on invasive (i.e., liver biopsy) or poorly available (i.e., Next-Generation Sequencing) approaches. A defective production of the iron regulatory hormone hepcidin is the key pathogenetic factor in hereditary hemochromatosis, irrespective of the gene involved, but extensive studies evaluating its potential diagnostic role are still lacking. This project evaluated hepcidin levels in a large subpopulation from the Cooperative Health Research In South Tyrol (CHRIS) study. Here we explored in particular hepcidin levels in subjects with altered iron status parameters, and their role in the identification of subjects at major risk of developing IO. Patients and Methods Study Population. The CHRIS study is a population-based study carried out in South Tyrol (Northern Italy), whose general aims are reported in detail elsewhere (Pattaro C, J Transl Med 2015). Blood samples were tested for several biochemical and genetic parameters, including those related to iron status, such as TSAT, ferritin, and C282Y and H63D mutations. Hepcidin was measured in stored aliquots by a recently updated and validated mass spectrometry-based method in tandem with liquid chromatography (LC-MS/MS), able to distinguish the active hepcidin-25 isoform (Diepeveen LE, Clin Chem Lab Med 2019). Results Among 4,642 participants, 6 were C282Y +/+ and 30 were C282Y-H63D (hereinafter defined as "HFE-H subjects"). HFE-H subjects showed ferritin levels only slightly higher than those with apparent wild-type HFE-H genotype (92.7 vs. 76.0 ng/ml, p=0.29), significantly higher TSAT (46.6 vs. 28.9%, p<0.0001) and lower hepcidin levels (1.41 vs. 2.30 nmol/l, p=0.016) (Table 1). Defective production of hepcidin was suggested by the reduced hepcidin:ferritin ratio (1.53 vs. 3.02 pmol/ng, p<0.0001), which was particularly low in C282Y +/+ (0.65 pmol/ng). Table 2 shows the prevalence of subjects with altered iron parameters (hyperferritinemia and/or increased TSAT), according to the HFE genotype. As concern HFE-H subjects, hyperferritinemia (i.e. >200 or >300 ng/ml in females and males, respectively) was detected in 16.7%, increased TSAT (>45%) in 52.8% and both in 11.1%. A biochemical pattern suggestive of IO (ferritin>500 ng/ml and TSAT>50%) was seen only in 33.3% of C282Y +/+ and in 6.7% of C282Y-H63D, while 41.7% neither had hyperferritinemia nor increased TSAT, confirming the low penetrance of such genotype. Although HFE-H subjects displayed a tendency to increase hepcidin production according to iron deposits (mean level of 1.10 nmol/l in subjects without hyperferritinemia/increased TSAT vs. 3.5 nmol/l of subjects with IO), the hepcidin:ferritin ratio was significantly lower in phenotypically expressed HFE-H subjects (0.49 vs. 2.04 pmol/ng, p=0.014) (Table 3). On the other hand, 540 participants (11.7 percent) without HFE-H genotype had hyperferritinemia, 64 (1.4%) had both hyperferritinemia and increased TSAT, and 12 (0.3 percent) had biochemical signs strongly suggestive of IO (ferritin>500 ng/ml and TSAT>50%). The latters had reduced hepcidin:ferritin ratio (0.92 pmol/ng), a value comparable to that of HFE-H iron loaded subjects (p=0.048). Whole Exome Sequencing data are available for the majority of CHRIS subjects included in this project and will be analyzed in detail in these subpopulations. Conclusions Our data suggest that the hepcidin:ferritin ratio may actually represent a useful indicator of hemochromatosis irrespective of the HFE genotype, possibly driving an optimal use of second level genetic test. Disclosures Girelli: Vifor Pharma: Other: honoraria for lectures; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; La Jolla Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy.

Randomized Phase II Study Evaluating the Efficacy and Safety of Deferasirox in Non-Transfusion-Dependent Thalassemia Patients with Iron Overload.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 5111-5111 ◽  
Author(s):  
Ali Taher ◽  
John B. Porter ◽  
Antonis Kattamis ◽  
Vip Viprakasit ◽  
Tomasz Lawniczek ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Iron Concentration ◽  
Transferrin Saturation ◽  
Safety Data ◽  
Efficacy And Safety ◽  
Thalassemia Intermedia ◽  
Advisory Committees

Abstract Abstract 5111 Background Clinically mild forms of thalassemia exist that, unlike β-thalassemia major, require no or only infrequent transfusions (eg. β-thalassemia intermedia, HbH disease). However, due to increased gastrointestinal iron absorption secondary to ineffective erythropoiesis these patients may still develop iron overload. For example, thalassemia intermedia patients (n=74) within a cross-sectional study had a mean serum ferritin (SF) of 1023 ng/mL (range 15–4140) and a mean liver iron concentration (LIC) of 9 mg Fe/g dw (range 0.5–32.1) at baseline despite most being transfusion-naïve (n=20) or rarely transfused (n=45), and only nine receiving regular transfusions (2–4 times/yr) (Taher et al. ITIFPaP: 13th International TIF Conference for Thalassaemia Patients & Parents, October 8–11 2008, Singapore, poster number MON04). Non-transfusional iron overload leads to the same serious clinical sequelae as transfusional iron overload, including liver, cardiac and endocrine dysfunctions. As patients with non-transfusional iron overload are not candidates for phlebotomy due to their underlying anemia, chelation therapy is the only available option for decreasing their iron burden. However, there is currently limited data available on the use of chelation in this population. The once-daily oral iron chelator deferasirox (Exjade®) is currently approved for the treatment of iron overload in patients with transfusion-dependent anemia. This prospective, randomized, double-blind, placebo-controlled Phase II ‘THALASSA’ study will evaluate the efficacy and safety of deferasirox in patients with non-transfusion-dependent thalassemia. Methods Non-transfusion-dependent thalassemia patients aged ≥10 yrs will be randomized 2:1:2:1 to starting doses of deferasirox/placebo 5 mg/kg/day/ deferasirox/placebo 10 mg/kg/day over a planned 12-month treatment period. Doses can be doubled after 6 months should patients require a higher dose, which will be determined after 6 months of treatment. All patients are required to have a baseline LIC of ≥5 mg Fe/g dw, as measured by R2 magnetic resonance imaging, and SF levels of >300 ng/mL. Patients will be excluded if they have: anticipated regular transfusions during the study (sporadic transfusions, such as in cases of infection, are allowed); any transfusion within 6 months prior to study start, chelation within 1 month prior to study start; HbS variants of thalassemia; impaired renal and liver function. Primary efficacy endpoint is absolute change from baseline in LIC at 12 months; secondary efficacy endpoints include change from baseline in LIC after 6 months and in SF after 6 and 12 months, as well as change in hematological and iron metabolism parameters (eg hemoglobin, transferrin saturation). Safety assessments include adverse event and laboratory parameter monitoring. 156 patients are planned for inclusion. Results As of 3 August 2009, 18 sites had been activated. Sites currently activated are in Thailand (n=5), Turkey (n=4), Italy (n=3), Malaysia (n=2), UK (n=2) Lebanon (n=1). Fifty-seven patients have been randomized to either deferasirox or placebo and their demographic data are shown in Table 1. Conclusions Similar to transfusion-dependent thalassemia patients, non- transfusion-dependent thalassemia patients also develop iron overload. This ongoing study will generate prospective efficacy and safety data for the use of deferasirox in non-transfusion-dependent thalassemia patients with iron overload. To prevent long term complications due to iron overload, it is important to assess iron chelation in this patient population as they are not candidates for phlebotomy due to the underlying anemia. Disclosures Taher: Novartis: Honoraria, Research Funding. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau. Viprakasit:Thai Government: Employment; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Government Pharmaceutical Organization of Thailand: Honoraria, Research Funding. Lawniczek:Novartis Pharma AG: Employment. Pereno:Novartis Pharma AG: Employment. Schoenborn-Kellenberger:Novartis Pharma AG: Employment. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Mitapivat Improves Ineffective Erythropoiesis and Reduces Iron Overload in Patients with Pyruvate Kinase Deficiency

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2005-2005
Author(s):  
Eduard J. Van Beers ◽  
Hanny Al-Samkari ◽  
Rachael F. Grace ◽  
Wilma Barcellini ◽  
Andreas Glenthoej ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Pyruvate Kinase ◽  
Research Funding ◽  
Iron Concentration ◽  
Transferrin Saturation ◽  
Controlled Study ◽  
Publicly Traded ◽  
Ineffective Erythropoiesis ◽  
Advisory Committees

Abstract Background: Pyruvate kinase (PK) deficiency is a rare hereditary disease resulting in chronic hemolytic anemia, which is associated with serious complications, including iron overload, regardless of transfusion status. Ineffective erythropoiesis is linked to iron overload in patients (pts) with hemolytic anemias. Mitapivat is a first-in-class, oral, allosteric activator of the red blood cell PK enzyme (PKR) that has demonstrated improvement in hemoglobin (Hb), hemolysis, and transfusion burden in pts with PK deficiency. This analysis assessed the effect of mitapivat on markers of erythropoiesis and iron overload in pts with PK deficiency enrolled in 2 phase 3 studies, ACTIVATE (NCT03548220) and ACTIVATE-T (NCT03559699), and the long-term extension (LTE) study (NCT03853798). Methods: In ACTIVATE (double-blind, placebo-controlled study), 80 pts (age ≥ 18 years [yrs]) with a confirmed diagnosis of PK deficiency who were not regularly transfused (≤ 4 transfusion episodes in the prior yr; none in the prior 3 months) were randomized to receive mitapivat or placebo. In ACTIVATE-T (open-label, single-arm study), 27 pts (age ≥ 18 yrs) with a confirmed diagnosis of PK deficiency who were regularly transfused (≥ 6 transfusion episodes in the prior yr) were treated with mitapivat. Pts who completed either trial (24 weeks [wks] [ACTIVATE], 40 wks [ACTIVATE-T]) were eligible to continue in the LTE. Erythropoiesis markers included erythropoietin (EPO), erythroferrone, reticulocytes, and soluble transferrin receptor (sTfR). Markers of iron overload included hepcidin, iron, transferrin saturation (TSAT), ferritin, and liver iron concentration (LIC) by magnetic resonance imaging (MRI). In the LTE all pts received mitapivat. Pts from ACTIVATE were categorized into either the mitapivat-to-mitapivat arm (M/M) or the placebo-to-mitapivat arm (P/M). The ACTIVATE-T/LTE analysis includes pts who achieved transfusion-free status in ACTIVATE-T. The ACTIVATE/LTE analysis assessed change in markers from baseline (BL) over time in both study arms. Results: Eighty pts were included in the ACTIVATE/LTE analysis (M/M = 40; P/M = 40). Pts in both arms had abnormal BL erythropoiesis markers consistent with underlying ineffective erythropoiesis, and BL abnormal markers of iron overload. In the M/M arm, mean (SD) EPO, erythroferrone, reticulocytes, and sTfR decreased from BL to Wk 24 of mitapivat treatment by -32.9 IU/L (62.47), -9834.9 ng/L (13081.15), -202.0 10 9/L (246.97), and -56.0 nmol/L (82.57), respectively, while they remained stable or increased in the P/M arm on placebo (Figure). Twenty-four wks after starting mitapivat in the LTE (Wk 48 post BL), pts in the P/M arm had comparable beneficial decreases in mean (SD) EPO, erythroferrone, reticulocytes, and sTfR of -11.6 IU/L (30.74), -9246.1 ng/L (8314.17), -283.7 10 9/L (374.27), and -38.7 nmol/L (48.37), respectively. Improvements in hepcidin, iron, TSAT, and LIC were also observed with mitapivat treatment; ferritin remained stable (Table). Mean (SD) hepcidin increased in the M/M arm at Wk 24 and in the P/M arm 24 wks after starting mitapivat (Wk 48 post BL). At Wk 24, mean (SD) iron and TSAT, and median (Q1, Q3) LIC decreased in the M/M arm, while they increased on placebo. In the P/M arm, iron, TSAT, and LIC decreased 24 wks after starting mitapivat (Wk 48 post BL). Transfusion-free responders from ACTIVATE-T (n = 6) also experienced improvements in markers of erythropoiesis and iron overload in the LTE. Conclusions: In addition to improving Hb, hemolysis, and transfusion burden, data from ACTIVATE, ACTIVATE-T, and the LTE study indicate that activation of PKR with mitapivat improves markers of ineffective erythropoiesis and iron homeostasis in PK deficiency, thereby decreasing iron overload in these pts. Mitapivat has the potential to become the first approved therapy in PK deficiency with beneficial effect on iron overload. Figure 1 Figure 1. Disclosures Van Beers: Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; RR Mechatronics: Research Funding; Pfizer: Research Funding. Al-Samkari: Amgen: Research Funding; Argenx: Consultancy; Rigel: Consultancy; Novartis: Consultancy; Dova/Sobi: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Moderna: Consultancy. Grace: Agios: Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Principia: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Barcellini: Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria; Novartis: Honoraria; Agios: Honoraria, Research Funding. Glenthoej: Bluebird Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Research Funding; Novo Nordisk: Honoraria. Judge: Agios Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Kosinski: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Xu: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Beynon: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. McGee: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Porter: La Jolla Pharmaceuticals: Honoraria; Protagonism: Honoraria; Agios: Consultancy, Honoraria; bluebird bio, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene (BMS): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Vifor: Honoraria, Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kuo: Celgene: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Research Funding; Bluebird Bio: Consultancy; Apellis: Consultancy.

Serum Ferritin, Labile Plasma Iron and Transferrin Saturation: Comparison Between Underlying Anemias with Transfusional Iron Overload Before and After Treatment with Deferasirox.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2126-2126 ◽  
Author(s):  
John B Porter ◽  
Mohsen Elalfy ◽  
Vip Viprakasit ◽  
Stephane Giraudier ◽  
Lee Lee Chan ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Serum Ferritin ◽  
Research Funding ◽  
Full Range ◽  
Transferrin Saturation ◽  
Iron Chelation ◽  
Serum Markers ◽  
Advisory Committees ◽  
The Relationship

Abstract Abstract 2126 Background: In patients with transfusion-dependent anemias, monitoring the efficacy of iron chelation therapy (ICT) using serum ferritin (SF) alone can sometimes be challenging; therefore, additional serum markers would be helpful. Furthermore, any differences between different anemias for the relationship between SF and other serum markers both before and in response to ICT may be useful to predict relative risk of iron-mediated toxicity between these conditions. Data from the 1-yr EPIC (Evaluation of Patients' Iron Chelation with Exjade®) trial allows assessment of iron parameters in a large cohort of patients with thalassemia, myelodysplastic syndromes (MDS) and sickle cell disease (SCD). Here we evaluate trends in liver iron concentration (LIC), transferrin saturation (TfSat) and labile plasma iron (LPI) in their relation to SF levels and assess systematic differences between underlying anemias. Relationships were assessed at baseline (BL), reflecting iron accumulation at study entry, and also at end of study (EOS), with changes reflecting iron excretion after 1 yr treatment with deferasirox. Methods: LIC, TfSat and LPI were measured at BL and at EOS for each underlying disease. Changes in these parameters as well as relationships between these parameters and SF were assessed by SF categories at BL and at EOS. For EOS measurements, last observation carried forward was used for all parameters (last post-BL available value), except for LPI, for which 1-yr visit was used. Pre-deferasirox dose LPI levels are reported. Results: Data from 1114 thalassemia patients, 336 MDS patients and 80 SCD patients were available for analysis. For all underlying anemias, LIC was higher at higher SF categories; in thalassemia patients for eg, with BL SF categories <1000, 1000–2000, 2000–3000, 3000–4000, 4000–5000, >5000 ng/mL, the mean LIC values at BL were 4.9, 9.0, 15.3, 22.1, 27.2, 32.5 mg Fe/g dw, respectively. Overall, mean TfSat was 89.6% (n=755) in thalassemia patients at BL and 96.1% (n=955) at EOS, compared with 82.5% (n=116) and 83.8% (n=171) in MDS patients, respectively. In SCD patients, TfSat was 61.3% (n=71) at BL and 64.1% (n=74) at EOS. TfSat was lowest in SCD patients across the full range of SF categories examined (Figure). At BL, TfSat was higher at higher SF categories in all diseases, with a similar trend at EOS, although at EOS this trend was more evident in MDS and SCD (Figure). Overall, mean LPI levels at BL and EOS were 1.25 μmol/L (n=472) and 0.59 μmol/L (n=818) in thalassemia patients, 0.53 μmol/L (n=221) and 0.14 μmol/L (n=147) in MDS patients, and 0.11 μmol/L (n=55) and 0.10 μmol/L (n=46) in SCD patients, respectively. LPI levels were highest in patients with thalassemia and lowest in SCD patients across SF categories (Figure). After 1 yr treatment with deferasirox, LPI levels were reduced in thalassemia and MDS patients, but there was no difference in patients with SCD. LPI was higher at higher SF categories in MDS patients at both BL and EOS, with a similar trend in SCD patients at EOS, although there was little relationship in thalassemia patients (Figure). Discussion: At matched SF levels and across a wide range of SF values, TfSat was lower in SCD patients, in comparison to thalassemia and MDS patients, both at BL and EOS. Similar observations have been reported previously and may contribute to the lower propensity for extra-hepatic iron accumulation in SCD patients. The mechanisms for this difference remain unclear, but could be attributed to sequestering of iron due to chronic inflammation in SCD. TfSat did not appear to decrease after 1 yr treatment with deferasirox, in any underlying anemia. The relationship of LPI to SF categories differed between underlying anemias; both at BL and EOS. At BL, SCD patients had low LPI values across the full range of measured SF values, whereas higher LPI levels at higher SF categories were most evident in MDS patients. Overall, LPI was highest in thalassemia patients. After 1 yr treatment with deferasirox, LPI was decreased in thalassemia and to a lesser extent in MDS patients, but there was no change from the low level at BL in SCD patients. The decrease in LPI in MDS and thalassemia at EOS may reflect the effects of residual plasma chelator 1 day after the previous dose and/or the decrease in storage iron over 1 yr of treatment. With further evaluation, LPI could become a useful marker of iron overload and chelation response in patients with MDS and possibly thalassemia. Disclosures: Porter: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Viprakasit:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. El-Ali:Novartis: Employment. Martin:Novartis: Employment. Cappellini:Novartis: Speakers Bureau.

scholarly journals Iron Chelation and Ferritin below 500 Mcg/L in Transfusion Dependent Thalassemia: Beyond the Limits of Clinical Trials

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3542-3542 ◽  
Author(s):  
Natalia Scaramellini ◽  
Carola Arighi ◽  
Alessia Marcon ◽  
Dario Consonni ◽  
Elena Cassinerio ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Liver Function ◽  
Iron Overload ◽  
Board Of Directors ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Published Data ◽  
Iron Chelation Therapy ◽  
Iron Intake ◽  
Advisory Committees

Introduction The current therapeutic management of transfusion dependent thalassemia (TDT) is based on regular blood transfusion and iron chelation therapy. Transfusion iron overload remains one of the major causes of morbidity and mortality in these patients because of the accumulation in heart, liver and endocrine glands. Three iron chelators are available in clinical practice: deferoxamine (DFO), deferiprone(DFP) and deferasirox (DFX). Guidelines clearly recommend when to start iron chelation, while discontinuation criteria are not well defined. Authorised product information state that we should consider interrupting DFX if serum ferritin (SF) falls consistently below 500mcg/L. This cut off was arbitrarily determined and there are no studies evaluating the effects of chelators in presence of SF below 500 mcg/L. In our clinical practice at Rare Diseases center of Fondazione IRCCS Ca' Granda Policlinico in Milan we do not completely interrupt iron chelation in TDT patients for SF levels below 500 mcg/L. Aims and methods Aim of our study was to evaluate the appearance of adverse events due to the assumption of iron chelation therapy in those TDT patients who had SF below 500 mcg/L. In this study we retrospectively evaluated renal and liver function from 2008 throughout December 2018 in TDT patients on DFX who presented SF below 500 mcg/L for 24 consecutive months. DFX dose are all expressed with the new tablets formulation dose. We evaluated SF, iron intake, LIC and MIC, renal and hepatic function. .A total of 5076 observations were collected, with 99.5 average per patient. We evaluated the relationships among variables with correlation models with random intercept Results One hundred ninety-two TDT patients are regularly followed at our center. They receive regular transfusion treatment and iron chelation therapy to prevent secondary iron overload. 51 out of 192 patients (32 F, 19 M, aged 44 ± 7 years) treated with DFX presented mean SF below 500 mcg/L for at least 24 consecutive months. Hematological and iron status parameters are described in Table 1. We found a strong correlation between SF and LIC (p&lt;0.001) and for SF&lt;500 mcg/L no hepatic iron overload was observed. Conversely we did not found a correlation between SF and MIC. For SF values below 500 mcg/L there was a minimal increase in creatinine levels, however the mean creatinine values remained within the normal range.Moreover, creatinine variation between two consecutive evaluation was below 0.3 mg/dl, cut off for acute kidney injury. Similar results were observed for liver function. Although a minimal increase of mean ALT value was observed for SF below 500 mcg/L, it remained within the normal range. None of our patient showed ALT level indicative of liver damage (ALT&gt; 10 x upper limit of normal) We evaluated the relation between SF and DFX dose. Mean DFX dose decreases according to SF reduction. However, for SF value &lt; 240 mcg/L, DFX dose remained stable at an average of 14 mg/kg per day. Conclusion According to our preliminary data, administration of DFX in TDT patients in presence of SF below 500 mcg/L is safe. Creatinine and ALT fluctuations, that usually remain within the range of normality, are mild, and transient and do not require specific treatment. Consistently with previously published data by Cohen et al, we show that a mean dosage of DFX of 14 mg/Kg die of film-coated tablet (20 mg/Kg of dispersable formulation) are necessary to balance an iron intake of 0.3 mg/kg die in absence of iron overload. Based on these results we suggest that in TDT patients with a continuous iron intake, iron chelation should be continued even when ferritin is below 500mcg/L. Monitoring of liver and kidney function tests are recommended in patient's follow up, as well as tailoring iron chelation. Disclosures Cappellini: Vifor Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; Genzyme/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Motta:Sanofi-Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Dysmetabolic Hyperferritinemia: All Iron Overload Is Not Hemochromatosis

2015 ◽  
Vol 9 (1) ◽  
pp. 7-14 ◽  
Author(s):  
Jasbir Makker ◽  
Ahmad Hanif ◽  
Bharat Bajantri ◽  
Sridhar Chilimuri
Keyword(s):  
Iron Overload ◽  
Autosomal Recessive ◽  
Binding Capacity ◽  
Transferrin Saturation ◽  
Autosomal Recessive Disorder ◽  
Organ Damage ◽  
High Serum ◽  
Hemochromatosis Gene ◽  
Secondary Iron Overload ◽  
Iron Binding Capacity

Disturbances in iron metabolism can be genetic or acquired and accordingly manifest as primary or secondary iron overload state. Organ damage may result from iron overload and manifest clinically as cirrhosis, diabetes mellitus, arthritis, endocrine abnormalities and cardiomyopathy. Hemochromatosis inherited as an autosomal recessive disorder is the most common genetic iron overload disorder. Expert societies recommend screening of asymptomatic and symptomatic individuals with hemochromatosis by obtaining transferrin saturation (calculated as serum iron/total iron binding capacity × 100). Further testing for the hemochromatosis gene is recommended if transferrin saturation is >45% with or without hyperferritinemia. However, management of individuals with low or normal transferrin saturation is not clear. In patients with features of iron overload and high serum ferritin levels, low or normal transferrin saturation should alert the physician to other - primary as well as secondary - causes of iron overload besides hemochromatosis. We present here a possible approach to patients with hyperferritinemia but normal transferrin saturation.

Iron Overload in C282Y Heterozygotes: Identification of New Rare HFE Gene Mutants and a Step Strategy for Diagnosis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1859-1859
Author(s):  
Patricia Aguilar-Martinez ◽  
Severine Cunat ◽  
Fabienne Becker ◽  
Francois Blanc ◽  
Marlene Nourrit ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Status ◽  
Hereditary Hemochromatosis ◽  
Genetic Defect ◽  
Transferrin Saturation ◽  
Hfe Gene ◽  
Compound Heterozygous ◽  
Exon 2 ◽  
High Iron ◽  
Iron Parameters

Abstract Introduction: Homozygozity for the p.Cys282Tyr (C282Y) mutation of the HFE gene is the main genotype associated with the common form of adult hereditary hemochromatosis. C282Y carriers do not usually develop iron overload, unless they have additional risk factors such as liver diseases, a dysmetabolic syndrome or an associated genetic defect. The commonest is the compound heterozygous state for C282Y and the widespread p.His63Asp (H63D) variant allele. However, a few rare HFE mutations can be found on the 6th chromosome in trans, some of which are of clinical interest to fully understand the disorder. Patients and Methods: We recently investigated four C282Y carrier patients with unusually high iron parameters, including increased levels of serum ferritin (SF), high transferrin saturation (TS) and high iron liver content measured by MRI. They were males, aged 37, 40, 42, 47 at diagnosis. Two brothers (aged 40 and 42) were referred separately. The HFE genotype, including the determination of the C282Y, H63D and S65C mutations was performed using PCR-RFLP. HFE sequencing was undertaken using the previously described SCA method (1). Sequencing of other genes (namely, HAMP, HJV/HFE2, SLC40A1, TFR2) was possibly performed in a last step using the same method. Results: We identified three rare HFE mutant alleles, two of which are undescribed, in the four studied patients. One patient bore a 13 nucleotide-deletion in exon 6 (c.[1022_1034del13], p.His341_Ala345&gt;LeufsX119), which is predicted to lead to an abnormal, elongated protein. The two brothers had a substitution of the last nucleotide of exon 2 (c.[340G&gt;A], p.Glu114Lys) that may modify the splicing of the 2d intron. The third patient, who bore an insertion of a A in exon 4 (c.[794dupA],p.[trp267LeufsX80]), has already been reported (1). Discussion: A vast majority of C282Y carriers will not develop iron overload and can be reassured. However, a careful step by step strategy at the clinical and genetic levels may allow to correctly identify those patients deserving further investigation. First, clinical examination and the assessment of iron parameters (SF and TS) allow identifying C282Y heterozygotes with an abnormal iron status. Once extrinsic factors such as heavy alcohol intake, virus or a dysmetabolic syndrome have been excluded, MRI is very useful to authenticate a high liver iron content. Second, HFE genotype must first exclude the presence of the H63D mutation. Compound heterozygozity for C282Y and H63D, a very widespread condition in our area, is usually associated with mild iron overload. Third, HFE sequencing can be undertaken and may identify new HFE variants as described here. The two novel mutations, a frameshift modifying the composition and the length of the C terminal end of the HFE protein and a substitution located at the last base of an exon, are likely to lead to an impaired function of HFE in association with the C282Y mutant. However, it is noteworthy that three of the four patients were diagnosed relatively late, after the 4th decade, as it is the case for C282Y homozygotes. Three further unrelated patients are currently under investigation in our laboratory for a similar clinical presentation. Finally, it can be noted that in those patients who will not have a HFE gene mutant identified, analysis of other genes implicated in iron overload must be performed to search for digenism or multigenism. None of our investigated patients had an additional gene abnormality.

A Phase I/II, Open-Label, Dose-Escalation Trial of Once-Daily Oral Chelator Deferasirox to Treat Iron Overload in HFE-Related Hereditary Hemochromatosis: Final Results of the Core Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1514-1514 ◽  
Author(s):  
Pradyumna D. Phatak ◽  
Pierre Brissot ◽  
Herbert Bonkovsky ◽  
Mark Wurster ◽  
Lawrie Powell ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Research Funding ◽  
Hereditary Hemochromatosis ◽  
Advisory Committees ◽  
The Core ◽  
Upper Limit ◽  
Dose Dependent

Abstract Abstract 1514 Poster Board I-537 Background and aims Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by progressive iron overload through increased intestinal absorption. Phlebotomy treatment is the standard of care, but compliance is variable and some patients are poor candidates due to underlying medical disorders and/or poor venous access. An oral iron chelator such as deferasirox (Exjade®) may provide an alternative treatment option for HH patients. Methods This is an inter-patient dose-escalation study of deferasirox (5, 10, 15 and 20 mg/kg) administered daily for 24 weeks to C282Y HFE homozygous HH patients with a pre-treatment serum ferritin (SF) value of 300–2000 ng/mL, transferrin saturation ≥45% and no known history of cirrhosis. A 6-month extension of this trial has recently been completed. The primary endpoint is the incidence and severity of adverse events (AEs). Secondary endpoints include change in SF, time to SF normalization (<100 ng/mL), longitudinal course of SF, and pharmacokinetics of deferasirox. Results 49 patients were enrolled and 48 patients were treated (33 men, 16 women; mean age 50.6 years; mean of 3.1 years since HH diagnosis) with deferasirox 5 (n=11), 10 (n=15) or 15 mg/kg/day (n=23) for at least 24 weeks. 37 (75.5%) patients completed the study (10 [90.9%], 11 [73.3%]; 16 [69.6%] patients in the 5, 10 and 15 mg/kg/day groups, respectively. The most common reasons for discontinuation were AEs in 3 (20.0%) patients and 4 (17.4%) patients in the 10 and 15 mg/kg/day groups, respectively. Bayesian analysis and medical review were performed between dose escalations. Meaningful reductions in SF were observed across the first three dose groups (median decrease -31.1%, -52.8% and -55.4% in the 3 groups respectively), and escalation to 20 mg/kg/day was not undertaken. Time course of the SF decline was dose-dependent (Figure). AEs in the core were dose dependent and consistent with the known safety profile of deferasirox. The most common drug-related AEs (≥10% in all patients) reported were diarrhea in 1 (9%), 4 (27%) and 9 (39%) patients, nausea in 0 (0%), 2 (13%) and 4 (17%) patients and abdominal pain in 0 (0%), 2 (13%), 3 (13%) patients in the 5, 10 and 15 mg/kg/day groups, respectively. One patient had ALT >5X upper limit of normal, and 11 patients had serum creatinine ≥33% over baseline and upper limit of normal on two consecutive occasions. All resolved with dose cessation or modification. Conclusions The results from the CORE trial suggest that deferasirox doses of 5, 10 and 15 mg/kg/day are effective at reducing iron burden in HH patients. Based on the safety profile, only the 5 and 10 mg/kg/day doses are being considered for further study in this population. The results of the 24 week extension phase will be available at the time of the meeting. Larger studies are required to define the appropriate treatment regimen in HH. Disclosures Phatak: Novartis: Honoraria, Speakers Bureau. Brissot:Novartis: Honoraria, Research Funding. Bonkovsky:Boehringer-Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees; Clinuvel: Consultancy; Lundbeck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Research Funding; Merck: Research Funding; Roche: Research Funding; Vertex: Research Funding. Niederau:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Adams:Novartis: Honoraria. Griffel:Novartis: Employment, Equity Ownership. Lynch:Novartis Pharmaceuticals: Employment. Schoenborn-Kellenberger:Novartis Pharma AG: Employment.

Iron Overload Diminishes the Effectiveness of the Innate Immune Response in Thalassemia Major: a Possible Mechanism for Increased Infection Risk.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4071-4071
Author(s):  
Patrick B Walter ◽  
Paul R Harmatz ◽  
Annie Higa ◽  
David Killilea ◽  
Nancy Sweeters ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Immune Response ◽  
Iron Overload ◽  
Board Of Directors ◽  
Innate Immune Response ◽  
Research Funding ◽  
Innate Immune ◽  
Healthy Controls ◽  
Advisory Committees ◽  
Fluorescent Intensity

Abstract Abstract 4071 Poster Board III-1006 Introduction Infection is the second most common cause of death in thalassemia. The innate immune system provides a first line of defense against infection and specificity depends on pattern recognition receptors (PRRs) specific to microbial pathogens. One class of PRR called the toll-like receptors (TLRs) are important for transducing the signal for bacterial Lipopolysaccharide (LPS), resulting not only in cytokine production, but also in the control of extracellular iron levels through production of neutrophil gelatinase associated Lipocalin (NGAL). However, the exact role that NGAL plays and the expression level of PRRs are unknown in thalassemia. Thus, the goal in these studies is to investigate the relationship of iron overload to the innate immune cell expression of PRRs and NGAL in thalassemia. Patients and Methods Fifteen transfusion dependent thalassemia patients (11 – 29 yrs old) participating in the combination trial of deferasirox (an oral iron chelator) and deferoxamine were enrolled (Novartis sponsored CICL670AUS24T). Fasting blood samples were obtained i) at baseline after a 72 hr washout of chelator, and ii) at 6 and 12 months on study. Five healthy controls (13 - 18 yrs old) were also enrolled. Fresh monocytes were isolated using antibody-linked magnetic microbeads (Miltenyi Biotec Inc). Highly enriched populations of CD14+ monocytes were verified by flow cytometry. The expression of TLR4, also examined by flow cytometry is reported as the mean fluorescent intensity (MFI). In patients with thalassemia, liver iron concentration (LIC) was analyzed by biomagnetic susceptibility (“SQUID”, Ferritometer®). The plasma levels of NGAL were analyzed by ELISA. Results At baseline the expression of monocyte TLR4 (mean 18.8 ± 3.5 MFI) was reduced 30% compared to the healthy controls (mean 26.9 ± 7.6 MFI, p<0.05). The expression of TLR4 over the follow-up period of 52 weeks in patients receiving intensive combination chelator therapy significantly increased 27% / year (7 MFI / year, p=0.005). Interestingly the expression of monocyte TLR4 was negatively correlated with LIC (r=-0.6, p=0.04). Finally, thalassemia patients at baseline have significantly higher levels of NGAL (80 ± 20 ng/ml) compared to controls (42 ± 15 ng/ml, p=0.01). Conclusions These preliminary studies support the hypothesis that iron burden has a negative impact on the innate immune response in thalassemia as demonstrated by the decreased expression of TLR4. After intensive chelation, the levels of TLR4 increased, indicating that decreased iron overload with chelation may improve innate immune responsiveness. Finally, the iron transport protein NGAL is significantly elevated in thalassemia possibly acting to prevent essential iron uptake by pathogenic bacteria. Disclosures: Harmatz: Novartis: Research Funding; Apotex : Membership on an entity's Board of Directors or advisory committees; Ferrokin: Membership on an entity's Board of Directors or advisory committees. Vichinsky:Novartis: Consultancy, Research Funding.

Combined Chelation Therapy with Deferasirox and Deferoxamine In Transfusion-Dependent Thalassemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4269-4269 ◽  
Author(s):  
Ashutosh Lal ◽  
Nancy Sweeters ◽  
Vivian Ng ◽  
Drucilla Foote ◽  
Patricia Evans ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Research Funding ◽  
Chelation Therapy ◽  
Liver Weight ◽  
Myocardial Iron ◽  
Advisory Committees ◽  
Single Drug ◽  
Median Plasma ◽  
Group B

Abstract Abstract 4269 Therapeutic regimens that combine two iron chelators may enhance chelation efficiency by improving access to different tissue iron stores and control of the toxic labile iron pool. The combination of two chelators can reduce toxicity through averting the need for high doses of a single drug, but it is essential to establish the safety such regimens. We therefore explored the combined use of deferasirox (DSX) and deferoxamine (DFO) in patients with transfusion-dependent thalassemia who had failed standard chelation therapy with single drug. Patients were eligible if the liver iron concentration (LIC) >15 mg/g dry liver-weight or if iron-induced end organ injury was present. Subjects were monitored for hepatic and renal toxicity, visual or auditory changes, and the development of new complications from iron overload. The ability of the combined therapy to control systemic iron burden (serum ferritin and LIC) and myocardial iron overload (MRI T2*) was evaluated. We also measured changes in plasma levels of non-transferrin bound iron (NTBI) and labile plasma iron (LPI). Fifteen subjects were enrolled in 3 groups: adults with LIC <15 mg/g dry liver-weight (group A), adults with LIC >15 mg/g (group B), and children 8–18 years with LIC >5 mg/g (group C). The duration of therapy was 52 weeks. DSX (20-30 mg/Kg) was administered daily and DFO (35-50 mg/Kg/infusion) was infused on 3–7 days/week (as 8–12 hour infusion) based upon the degree of iron overload present at baseline. At the initiation of the study, the mean daily dose of DFO was 16, 33, and 17 mg/Kg/day and mean DSX dose was 21, 25 and 22 mg/Kg/day for groups A, B and C, respectively. At the conclusion of the trial, the median LIC declined by 48% from 10.8 mg/g (3.9-34.8 mg/g) to 5.7 mg/g (1.0-24.0 mg/g, p=0.003). The median ferritin fell by 43% from 2030 ng/mL (1000-5230 ng/mL) to 1150 ng/mL (421-5260 ng/mL, p=0.008). Myocardial iron in the 3 subjects who had T2* <20 msec at study entry (range 6.5–19.5 msec at week 0) showed an average improvement of +2.43 msec following treatment (range 8.8–21.3 msec at week 52, p=0.027). All 3 subjects with left ventricular ejection fraction below 60% at baseline (47.5-58.1%) showed improvement at end of study (60.6-64.4%). There was progressive decline in median plasma NTBI level during the study from 3.26 μM (1.79-5.79 μM) at baseline to 2.38 μM (1.59-3.08 μM) at 12 months (p=0.008). DSX produced immediate and significant decline in plasma NTBI when administered during infusion of DFO. The median plasma NTBI measured on DFO alone was 2.46 μM (0.92-5.90 μM), which decreased to 1.96 μM (0-3.50 μM) following administration of the dose of DSX (p<0.001). A sustained control of the LPI fraction was also demonstrated throughout the study period. At baseline the median LPI was 0.87 μM (0-2.43 μM) which decreased to 0.05 μM (0-1.20 μM) during the study period (p=0.004). No significant toxicity or unusual adverse events were observed with combined chelation therapy in this group of high-risk patients with thalassemia. Elevation of serum creatinine or ALT was not observed in any subject. One subject from group B died at 9 weeks from start of trial from sepsis. One subject interrupted DSX therapy because of abdominal pain. In all other cases the treatment was well tolerated and no dose adjustment or suspension of therapy was required on account of toxicity. Protocol-mandated modification of treatment (temporary cessation of DSX or DFO) occurred in three subjects owing to a marked fall in serum ferritin and LIC. These results suggest that simultaneous administration DSX and DFO is well tolerated and has low potential for toxicity. Combined chelation therapy appears to be effective in rapidly reducing systemic iron burden, lowering myocardial iron, and controlling plasma NTBI and LPI in patients at risk of developing end-organ damage. Disclosures: Harmatz: Ferrokin: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Vichinsky:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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