Hematologic responses to deferasirox therapy in transfusion-dependent patients with myelodysplastic syndromes

Background Reductions in transfusion requirements/improvements in hematologic parameters have been associated with iron chelation therapy in transfusion-dependent patients, including those with myelodysplastic syndromes; data on these reductions/improvements have been limited to case reports and small studies. Design and Methods To explore this observation in a large population of patients, we report a post-hoc analysis evaluating hematologic response to deferasirox in a cohort of iron-overloaded patients with myelodysplastic syndromes enrolled in the Evaluation of Patients’ Iron Chelation with Exjade® (EPIC) study using International Working Group 2006 criteria. Results Two-hundred and forty-seven, 100 and 50 patients without concomitant medication for myelodysplastic syndromes were eligible for analysis of erythroid, platelet and neutrophil responses, respectively. Erythroid, platelet and neutrophil responses were observed in 21.5% (53/247), 13.0% (13/100) and 22.0% (11/50) of the patients after a median of 109, 169 and 226 days, respectively. Median serum ferritin reductions were greater in hematologic responders compared with non-responders at end of study, although these differences were not statistically significant. A reduction in labile plasma iron to less than 0.4 μmol/L was observed from week 12 onwards; this change did not differ between hematologic responders and non-responders. Conclusions This analysis suggests that deferasirox treatment for up to 1 year could lead to improvement in hematologic parameters in some patients with myelodysplastic syndromes.

[1]  D. Steensma,et al.  Deferasirox reduces serum ferritin and labile plasma iron in RBC transfusion-dependent patients with myelodysplastic syndrome. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  D. Brizel,et al.  National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology , 2012 .

[3]  G. Bochicchio,et al.  Positive effects on hematopoiesis in patients with myelodysplastic syndrome receiving deferasirox as oral iron chelation therapy: a brief review. , 2011, Leukemia research.

[4]  G. Barosi,et al.  Clinical management of myelodysplastic syndromes: update of SIE, SIES, GITMO practice guidelines. , 2010, Leukemia research.

[5]  A. Ganser,et al.  Deferasirox in iron-overloaded patients with transfusion-dependent myelodysplastic syndromes: Results from the large 1-year EPIC study. , 2010, Leukemia research.

[6]  D. Cilloni,et al.  Deferasirox is a powerful NF-κB inhibitor in myelodysplastic cells and in leukemia cell lines acting independently from cell iron deprivation by chelation and reactive oxygen species scavenging , 2010, Haematologica.

[7]  E. Fibach,et al.  Changes in parameters of oxidative stress and free iron biomarkers during treatment with deferasirox in iron-overloaded patients with myelodysplastic syndromes , 2010, Haematologica.

[8]  G. Praticò,et al.  Iron chelation therapy associated with improvement of hematopoiesis in transfusion‐dependent patients , 2010, Transfusion.

[9]  M. Breccia,et al.  Deferasirox Treatment Interruption in a Transfusion-Requiring Myelodysplastic Patient Led to Loss of Erythroid Response , 2010, Acta Haematologica.

[10]  R. Ganetzky,et al.  Phase I combination trial of lenalidomide and azacitidine in patients with higher-risk myelodysplastic syndromes. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  M. Cappellini,et al.  Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC study of deferasirox in 1744 patients with transfusion-dependent anemias , 2010, Haematologica.

[12]  L. Vickars,et al.  Red Blood Cell Transfusion Independence Following the Initiation of Iron Chelation Therapy in Myelodysplastic Syndrome , 2009, Advances in hematology.

[13]  R. Haba,et al.  Effect of iron chelator deferasirox on chronic anemia and thrombocytopenia in a transfusion-dependent patient with myelodysplastic syndrome , 2010, International journal of hematology.

[14]  D. Cilloni,et al.  Deferasirox is a powerful NF-κ B inhibitor in myelodysplastic cells and in leukemia cell lines acting independently from intracellular iron chelation and reactive oxygen species scavenging , 2010 .

[15]  D. Steensma,et al.  Two-Year Analysis of Efficacy and Safety of Deferasirox (Exjade®) Treatment in Myelodysplastic Syndrome Patients Enrolled in the US03 Study. , 2009 .

[16]  K. Ozawa,et al.  Hematopoietic recovery after administration of deferasirox for transfusional iron overload in a case of myelodysplastic syndrome. , 2009, [Rinsho ketsueki] The Japanese journal of clinical hematology.

[17]  J. Hainsworth,et al.  Hematologic response to three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  Yun Yen,et al.  NCCN clinical practice guidelines in oncology: hepatobiliary cancers. , 2009, Journal of the National Comprehensive Cancer Network : JNCCN.

[19]  S. Capalbo,et al.  Early Deferasirox Treatment in a Patient with Myelodysplastic Syndrome Results in a Long-Term Reduction in Transfusion Requirements , 2009, Acta Haematologica.

[20]  L. Arenillas,et al.  Independent Impact of Iron Overload and Transfusion Dependency on Survival and Leukemic Evolution in Patients with Myelodysplastic Syndrome , 2008 .

[21]  S. Ghaffari.  Oxidative stress in the regulation of normal and neoplastic hematopoiesis. , 2008, Antioxidants & redox signaling.

[22]  J. Bennett.  Consensus statement on iron overload in myelodysplastic syndromes , 2008, American journal of hematology.

[23]  D. Cilloni,et al.  Deferasirox Treatment Improved the Hemoglobin Level and Decreased Transfusion Requirements in Four Patients with the Myelodysplastic Syndrome and Primary Myelofibrosis , 2008, Acta Haematologica.

[24]  A. Raza,et al.  Combination of 5‐azacytidine and thalidomide for the treatment of myelodysplastic syndromes and acute myeloid leukemia , 2008, Cancer.

[25]  B. Leber,et al.  Iron overload in myelodysplastic syndromes: a Canadian consensus guideline. , 2008, Leukemia research.

[26]  M. Tomonaga,et al.  Japanese epidemiological survey with consensus statement on Japanese guidelines for treatment of iron overload in bone marrow failure syndromes , 2008, International journal of hematology.

[27]  H. Tamary,et al.  Iron chelation therapy in patients with myelodysplastic syndromes: consensus conference guidelines. , 2008, The Israel Medical Association journal : IMAJ.

[28]  Soo-Jeong Park,et al.  Complete Hematopoietic Recovery after Continuous Iron Chelation Therapy in a Patient with Severe Aplastic Anemia with Secondary Hemochromatosis , 2008, Journal of Korean medical science.

[29]  P. Valent,et al.  Iron overload in myelodysplastic syndromes (MDS) – diagnosis, management, and response criteria: a proposal of the Austrian MDS platform , 2008, European journal of clinical investigation.

[30]  A. Verma,et al.  Iron overload in myelodysplastic syndromes , 2008, Leukemia & lymphoma.

[31]  D. Steensma,et al.  Deferasirox (ICL670; Exjade®) Reduces Serum Ferritin (SF) and Labile Plasma Iron (LPI) in Patients with Myelodysplastic Syndromes (MDS). , 2007 .

[32]  M. Cazzola,et al.  Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  E. Angelucci,et al.  Correction of anemia in a transfusion-dependent patient with primary myelofibrosis receiving iron chelation therapy with deferasirox (Exjade®, ICL670) , 2007, European journal of haematology.

[34]  B. Cheson,et al.  Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. , 2006, Blood.

[35]  S. Nimer,et al.  Clinical management of myelodysplastic syndromes with interstitial deletion of chromosome 5q. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  G. Kroemer,et al.  NF-kappaB constitutes a potential therapeutic target in high-risk myelodysplastic syndrome. , 2006, Blood.

[37]  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.

[38]  G. Kroemer,et al.  NF-κB constitutes a potential therapeutic target in high-risk myelodysplastic syndrome , 2005 .

[39]  M. Cazzola,et al.  Myelodysplastic syndromes--coping with ineffective hematopoiesis. , 2005, The New England journal of medicine.

[40]  E. Frenkel,et al.  Unfractionated heparin, low molecular weight heparins, and pentasaccharide: basic mechanism of actions, pharmacology, and clinical use. , 2005, Hematology/oncology clinics of North America.

[41]  B. Aggarwal,et al.  Nuclear factor-kappaB: the enemy within. , 2004, Cancer cell.

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

[43]  G. Mufti,et al.  Guidelines for the diagnosis and therapy of adult myelodysplastic syndromes , 2003, British journal of haematology.

[44]  B. Cheson,et al.  Report of an international working group to standardize response criteria for myelodysplastic syndromes. , 2000, Blood.

[45]  F. Jensen,et al.  The effect of iron chelation on haemopoiesis in MDS patients with transfusional iron overload , 1996, British journal of haematology.

[46]  R. Holdrinet,et al.  Improvement of erythropoiesis during treatment with deferiprone in a patient with myelofibrosis and transfusional hemosiderosis , 1996, American journal of hematology.

[47]  R. Feelders,et al.  Iron chelators may enhance erythropoiesis by increasing iron delivery to haematopoietic tissue and erythropoietin response in iron-loading anaemia. , 1993, Acta haematologica.

[48]  J. Ellegaard,et al.  DESFERRIOXAMINE TREATMENT REDUCES BLOOD TRANSFUSION REQUIREMENTS IN PATIENTS WITH MYELODYSPLASTIC SYNDROME , 1992, British journal of haematology.