Labile plasma iron levels predict survival in patients with lower-risk myelodysplastic syndromes

Red blood cell transfusions remain one of the cornerstones in supportive care of lower-risk patients with myelodysplastic syndromes. We hypothesized that patients develop oxidant-mediated tissue injury through the formation of toxic iron species, caused either by red blood cell transfusions or by ineffective erythropoiesis. We analyzed serum samples from 100 lower-risk patients with myelodysplastic syndromes at six-month intervals for transferrin saturation, hepcidin-25, growth differentiation factor 15, soluble transferrin receptor, non-transferrin bound iron and labile plasma iron in order to evaluate temporal changes in iron metabolism and the presence of potentially toxic iron species and their impact on survival. Hepcidin levels were low in 34 patients with ringed sideroblasts compared to 66 patients without. Increases of hepcidin and non-transferrin bound iron levels were visible early in follow-up of all transfusion-dependent patient groups. Hepcidin levels significantly decreased over time in transfusion-independent patients with ringed sideroblasts. Increased soluble transferrin receptor levels in transfusion-independent patients with ringed sideroblasts confirmed the presence of ineffective erythropoiesis and suppression of hepcidin production in these patients. Detectable labile plasma iron levels in combination with high transferrin saturation levels occurred almost exclusively in patients with ringed sideroblasts and all transfusion-dependent patient groups. Detectable labile plasma iron levels in transfusion-dependent patients without ringed sideroblasts were associated with decreased survival. In conclusion, toxic iron species occurred in all transfusion-dependent patients and in transfusion-independent patients with ringed sideroblasts. Labile plasma iron appeared to be a clinically relevant measure for potential iron toxicity and a prognostic factor for survival in transfusion-dependent patients. clinicaltrials.gov Identifier: 00600860.

[1]  D. Girelli,et al.  Hepcidin in the diagnosis of iron disorders. , 2016, Blood.

[2]  M. Cappellini,et al.  New insights into transfusion-related iron toxicity : implications for the 1 oncologist 2 , 2015 .

[3]  D. Swinkels,et al.  Second international round robin for the quantification of serum non-transferrin-bound iron and labile plasma iron in patients with iron-overload disorders , 2016, Haematologica.

[4]  P. Fenaux,et al.  Validation of the revised international prognostic scoring system (IPSS‐R) in patients with lower‐risk myelodysplastic syndromes: a report from the prospective European LeukaemiaNet MDS (EUMDS) registry , 2015, British journal of haematology.

[5]  P. Campbell,et al.  SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts. , 2015, Blood.

[6]  R. M. de Freitas,et al.  HFE gene mutation and oxidative damage biomarkers in patients with myelodysplastic syndromes and its relation to transfusional iron overload: an observational cross-sectional study , 2015, BMJ Open.

[7]  L. Hofbauer,et al.  Myelodysplasia is in the niche: novel concepts and emerging therapies , 2014, Leukemia.

[8]  A. Verma,et al.  Impact of iron overload and potential benefit from iron chelation in low-risk myelodysplastic syndrome. , 2014, Blood.

[9]  E. Nemeth,et al.  Molecular liaisons between erythropoiesis and iron metabolism. , 2014, Blood.

[10]  Bing Li,et al.  Serum iron metabolism and erythropoiesis in patients with myelodysplastic syndrome not receiving RBC transfusions. , 2014, Leukemia research.

[11]  Z. Cabantchik.  Labile iron in cells and body fluids: physiology, pathology, and pharmacology , 2014, Front. Pharmacol..

[12]  T. Ganz.  Systemic iron homeostasis. , 2013, Physiological reviews.

[13]  U. Germing,et al.  Serum hepcidin measured with an improved ELISA correlates with parameters of iron metabolism in patients with myelodysplastic syndrome , 2013, Annals of Hematology.

[14]  E. Nemeth.  Hepcidin and β-thalassemia major. , 2013, Blood.

[15]  S. Zeinali,et al.  Evaluation and Comparison of Soluble Transferrin Receptor in Thalassemia Carriers and Iron Deficient Patients , 2013, Hemoglobin.

[16]  Wei Zhang,et al.  ZIP14 and DMT1 in the liver, pancreas, and heart are differentially regulated by iron deficiency and overload: implications for tissue iron uptake in iron-related disorders , 2013, Haematologica.

[17]  P. Campbell,et al.  Inappropriately low hepcidin levels in patients with myelodysplastic syndrome carrying a somatic mutation of SF3B1 , 2013, Haematologica.

[18]  P. Fenaux,et al.  Hematologic responses to deferasirox therapy in transfusion-dependent patients with myelodysplastic syndromes , 2012, Haematologica.

[19]  Vip Viprakasit,et al.  Deferasirox reduces iron overload significantly in nontransfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study. , 2012, Blood.

[20]  P. Brissot,et al.  Non-transferrin bound iron: a key role in iron overload and iron toxicity. , 2012, Biochimica et biophysica acta.

[21]  P. Ponka,et al.  Iron overload in human disease. , 2012, The New England journal of medicine.

[22]  S. Sheth,et al.  Transfusion of human volunteers with older, stored red blood cells produces extravascular hemolysis and circulating non-transferrin-bound iron. , 2011, Blood.

[23]  K. Saigo,et al.  Oxidative Stress Levels in Myelodysplastic Syndrome Patients: Their Relationship to Serum Ferritin and Haemoglobin Values , 2011, The Journal of international medical research.

[24]  Tomas Ganz,et al.  Hepcidin and iron regulation, 10 years later. , 2011, Blood.

[25]  D. Girelli,et al.  Heparin: a potent inhibitor of hepcidin expression in vitro and in vivo. , 2011, Blood.

[26]  D. Girelli,et al.  Hepcidin Levels and Their Determinants in Different Types of Myelodysplastic Syndromes , 2010, PloS one.

[27]  M. Speeckaert,et al.  Biological and clinical aspects of soluble transferrin receptor , 2010, Critical reviews in clinical laboratory sciences.

[28]  Ning Zhang,et al.  Transfusion of red blood cells after prolonged storage produces harmful effects that are mediated by iron and inflammation. , 2010, Blood.

[29]  D. Swinkels,et al.  Recent advances in the understanding of iron overload in sideroblastic myelodysplastic syndrome , 2010, British journal of haematology.

[30]  C. Begley,et al.  Antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia. , 2010, Blood.

[31]  N. Gattermann,et al.  Iron overload in MDS—pathophysiology, diagnosis, and complications , 2010, Annals of Hematology.

[32]  André M. N. Silva,et al.  Influence of non-enzymatic post-translation modifications on the ability of human serum albumin to bind iron. Implications for non-transferrin-bound iron speciation. , 2009, Biochimica et biophysica acta.

[33]  M. Docquier,et al.  Growth differentiation factor 15 production is necessary for normal erythroid differentiation and is increased in refractory anaemia with ring‐sideroblasts , 2009, British journal of haematology.

[34]  D. Steensma,et al.  Neither serum ferritin nor the number of red blood cell transfusions affect overall survival in refractory anemia with ringed sideroblasts , 2008, American journal of hematology.

[35]  C. Pascutto,et al.  WHO classification and WPSS predict posttransplantation outcome in patients with myelodysplastic syndrome: a study from the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). , 2008, Blood.

[36]  M. Cazzola,et al.  Erythropoietin and granulocyte-colony stimulating factor treatment associated with improved survival in myelodysplastic syndrome. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  H. Dombret,et al.  Predictive factors of response and survival in myelodysplastic syndrome treated with erythropoietin and G-CSF: the GFM experience. , 2008, Blood.

[38]  E. Fibach,et al.  Oxidative stress in red blood cells, platelets and polymorphonuclear leukocytes from patients with myelodysplastic syndrome , 2007, European journal of haematology.

[39]  C. Rapisarda,et al.  Nature of non-transferrin-bound iron: studies on iron citrate complexes and thalassemic sera , 2007, JBIC Journal of Biological Inorganic Chemistry.

[40]  S. Goh,et al.  High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin , 2007, Nature Medicine.

[41]  R. Hehlmann,et al.  The soluble transferrin receptor in dysplastic erythropoiesis in myelodysplastic syndrome , 2007, European journal of haematology.

[42]  Yi Fang Liu,et al.  Ineffective erythropoiesis in beta-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin. , 2006, Blood.

[43]  E. Fibach,et al.  Oxidative Stress in Red Blood Cells, Platelets and Polymorphonuclear Leukocytes from Patients with Myelodysplastic Syndrome. , 2006 .

[44]  S. Rivella,et al.  Role of Iron in Inducing Oxidative Stress in Thalassemia: Can It Be Prevented by Inhibition of Absorption and by Antioxidants? , 2005, Annals of the New York Academy of Sciences.

[45]  Luca Malcovati,et al.  Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[46]  M. Pouchard,et al.  Redox active plasma iron in C282Y/C282Y hemochromatosis. , 2005, Blood.

[47]  E. Rachmilewitz,et al.  MEDICAL PROGRESS : β-thalassemia , 2005 .

[48]  Z. Cabantchik,et al.  Labile plasma iron (LPI) as an indicator of chelatable plasma redox activity in iron-overloaded beta-thalassemia/HbE patients treated with an oral chelator. , 2004, Blood.

[49]  Z. Cabantchik,et al.  Labile plasma iron in iron overload: redox activity and susceptibility to chelation. , 2003, Blood.

[50]  N. Breslau,et al.  Graphing survival curve estimates for time‐dependent covariates , 2002, International journal of methods in psychiatric research.

[51]  W. Breuer,et al.  The importance of non-transferrin bound iron in disorders of iron metabolism. , 2000, Transfusion science.

[52]  G. Link,et al.  Pathophysiology of Iron Overload a , 1998, Annals of the New York Academy of Sciences.

[53]  T Hamblin,et al.  International scoring system for evaluating prognosis in myelodysplastic syndromes. , 1997, Blood.

[54]  T. Yasuda,et al.  An improved simple colorimetric method for quantitation of non-transferrin-bound iron in serum. , 1995, Biochemistry and molecular biology international.

[55]  D. Bowen,et al.  Estimation of effective and total erythropoiesis in myelodysplasia using serum transferrin receptor and erythropoietin concentrations, with automated reticulocyte parameters. , 1994, Leukemia.

[56]  P. Pootrakul,et al.  Intact transferrin receptors in human plasma and their relation to erythropoiesis. , 1990, Blood.

[57]  H. Gralnick,et al.  Proposals for the classification of the myelodysplastic syndromes , 1982, British journal of haematology.

[58]  E. Rachmilewitz,et al.  Non‐Specific Serum Iron in Thalassaemia: an Abnormal Serum Iron Fraction of Potential Toxicity , 1978, British journal of haematology.