Hematologic improvement with iron chelation therapy in myelodysplastic syndromes: Clinical data, potential mechanisms, and outstanding questions. (September 2019)

• Record Type: Journal Article
• Authors: Leitch, Heather A.; Gattermann, Norbert
• Is Part Of: Critical reviews in oncology/hematology. Volume 141(2019)
• Page Start: 54
• Page End: 72
• Publication Date: 2019-09
• Subjects: αKG α-ketoglutarate -- AML acute myeloid leukemia -- AMPK adenosine monophosphate kinase -- ARNT aryl hydrocarbon receptor nuclear translocator, also known as hypoxia inducible factor 1β -- BCL-2 B-cell lymphoma 2 -- BFU-E burst forming unit erythroid -- β-TM β-thalassemia major -- c-FOS cellular FBJ osteosarcoma virus -- CFU-E colony-forming unit erythroid -- CFU-GM colony-forming unit granulocyte macrophage -- CFU-Mix colony-forming unit mix -- CXCL12 C-X-C motif chemokine 12 -- Cys cysteine -- DFO deferoxamine -- DFP deferiprone -- DFX deferasirox -- DMT1 divalent metal transporter 1 -- DNA deoxynucleic acid -- dROM derivatives of reactive oxygen metabolites -- DSB double strand breaks -- E2F1 E2F transcription factor 1 -- eLPI enhanced labile plasma iron -- ETC electron transport chain -- EPO erythropoietin -- ESA erythropoiesis-stimulating agents -- FAB French-American-British -- Fe2+ ferrous -- Fe3+ ferric -- Fe–S iron–sulfur cluster -- GCS γ-glutamyl cysteine synthetase heavy subunit -- GDF growth differentiation factor -- GI gastrointestinal -- GLUD glutamate dehydrogenase -- GLUL glutamate-ammonia ligase -- GM-CSF granulocyte macrophage colony-stimulating factor -- GPX glutathione peroxidase -- GRIM genes associated with the retinoid-interferon-induced mortality -- GSH glutathione -- H- heavy -- H2O2 hydrogen peroxide -- HI hematologic improvement -- HIF-1ɑ hypoxia inducible factor 1α -- HMA hypomethylating agent -- HOX homeobox -- HPC hematopoietic progenitor cell -- HSC hematopoietic stem cell -- HSPC hematopoietic stem/progenitor cell -- IC50 50% inhibitory concentration -- ICAM intracellular cell adhesion molecule -- ICT iron chelation therapy -- IOL iron overload -- IκBα nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor, α -- iNOS inducible nitric oxide synthase -- IPSS International Prognostic Scoring System -- IRE iron response element -- IRP iron responsive protein -- IWG International Working Group -- JNK c-Jun N-terminal kinase -- L- light -- LCI labile cellular iron -- LDH lactate dehydrogenase -- LIP labile iron pool -- LPI labile plasma iron -- MAPK mitogen activated protein kinase -- MCV mean cellular volume -- MDA malonyldialdehyde -- MDS myelodysplastic syndrome -- MDS-CI MDS comorbidity index -- MnSOD manganese superoxide dismutase -- mRNA messenger ribonucleic acid -- MSC mesenchymal stem/stromal cells -- mTOR mammalian target of rapamycin -- NAC N-acetyl cysteine -- NADP/H nicotinamide adenine dinucleotide phosphate (oxidized, H = reduced) -- NFκB nuclear factor κB -- NK natural killer -- NOX NADP/H oxidase -- NRAS neuroblastoma retrovirus-associated DNA sequences -- NS not significant -- NTBI non-transferrin bound iron -- NUP nuclear pore complex protein -- OCT-4 octamer-binding transcription factor, also known as POU5F1 -- OGG1 8-oxoguanine glycosylase -- OS overall survival -- PKC protein kinase C -- POU5F1 OCT-4, octamer-binding transcription factor -- PYGL glycogen phosphorylase, liver form -- RANTES regulated on activation, normal T cell expressed and secreted -- RBC red blood cell -- RCMD refractory cytopenia with multilineage dysplasia -- REDD1 regulated in development and DNA damage response 1 -- RES reticuloendothelial system -- Rev-1 DNA repair protein -- RIP receptor interacting protein -- ROS reactive oxygen species -- SCF stem cell factor -- SCT stem cell transplantation -- SF serum ferritin -- SOX sex determining region Y-box -- STAT signal transducer and activator of transcription -- Tc1 cytotoxic T cell type 1 -- Tc2 cytotoxic T cell type 2 -- TCA tricarboxylic acid -- TfR transferrin receptor -- Th1 T helper cell type 1 -- Th2 T helper cell type 2 -- TLR toll like receptor -- TNF tumor necrosis factor -- Treg regulatory T cell -- TSC tuberous sclerosis -- VEGF vascular endothelial growth factor -- WHO World Health Organization -- 2-HG 2-hydroxyglutarate -- 8-OG 7, 8-dihydro-8-oxoguanine -- 8-OH-dG 8-hydroxy-2′-deoxyguanosine; Hematologic improvement -- Iron chelation therapy -- Iron overload -- MDS -- Oxidative stress; Oncology -- Periodicals; Hematology -- Periodicals; 616.994
• DOI: 10.1016/j.critrevonc.2019.06.002
• Languages: English
• ISSNs: 1040-8428

Abstract

Highlights: MDS are clonal stem cell disorders often requiring red blood cell (RBC) transfusion. RBC transfusion results in iron overload, which portends inferior clinical outcomes. Studies of iron chelation in MDS show hematologic improvement (HI) in some patients. We review clinical data on hematologic improvement with iron chelation therapy in MDS. We review mechanisms by which HI may occur & identify areas for future investigation. Abstract: Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by cytopenias and progression to acute myeloid leukemia (AML). Although several treatments for MDS are available, the mainstay of therapy for most patients remains supportive care. This includes red blood cell (RBC) transfusion to correct anemia, which leads to iron overload. RBC transfusion dependence and iron overload portend inferior overall survival. Some studies indicate that iron chelation therapy (ICT) may have beneficial effects on clinical endpoints in MDS; however, these data are from non-randomized trials and the validity of the results is vigorously debated. A consistent observation in clinical studies of ICT in MDS has been hematologic improvement (HI) in some patients, including a reduction in RBC transfusion requirements and even transfusion independence. Here, we review data on HI with ICT in lower risk MDS, preclinical data examining mechanisms by which HI may occur, and identify areas for future investigation.