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Editorials
report demonstrated that the use of insecticide to impreg- nate bed nets and screening for parasites in blood reduced the malaria risk in children on iron supplementation.17 Moreover, recent data demonstrate that iron deficiency negatively impacts on immunological responses to diphthe- ria vaccine leaving children insufficiently protected against such infections (N Stoffel, Zurich, oral presentation, Bioiron Meeting 2019). Thus, this study by Armitage15 and co-work- ers is an important step forward to gain more insights into the relative contribution of different regulatory mecha- nisms on circulating biomarker concentrations such as hep- cidin and how this impacts on predicting therapeutic effica- cy and the risk:benefit ratio of iron supplementation in a primary care setting.
Future studies will have to clarify the optimal timing and dose of iron supplementation to children, whether or not a continuous administration via dietary iron fortification or a once daily or once every other day application is preferable.18 It will also be necessary to identify those chil- dren who might be at risk of unwanted effects of iron sup- plementation mainly arising from an increased morbidity and mortality from infections. Finally, we await further information on the impact of iron supplementation on growth and mental development, functionality of the immune system, efficacy of preventive measures such as vaccination, and the consequences of iron-mediated alter- ations of the intestinal microbiota on children’s health.
References
1. Muckenthaler MU, Rivella S, Hentze MW, Galy B. A Red Carpet for Iron Metabolism. Cell. 2017;168(3):344-361.
2. CamaschellaC.Irondeficiency.Blood.2019;133(1):30-39.
3. Weiss G, Carver PL. Role of divalent metals in infectious disease sus-
ceptibility and outcome. Clin Microbiol Infect. 2018;24(1):16-23.
4. Armitage AE, Drakesmith H. Genetics. The battle for iron. Science. 2014;346(6215):1299-1300.
5. SoaresMP,WeissG.TheIronageofhost-microbeinteractions.EMBO Rep. 2015;16(11):1482-1500.
6. Gwamaka M, Kurtis JD, Sorensen BE, et al. Iron deficiency protects against severe Plasmodium falciparum malaria and death in young chil- dren. Clin Infect Dis. 2012;54(8):1137-1144.
7. Girelli D, Nemeth E, Swinkels DW. Hepcidin in the diagnosis of iron disorders. Blood. 2016;127(23):2809-2813.
8. Theurl I, Aigner E, Theurl M, et al. Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood. 2009;113(21):5277-5286.
9. PaganiniD,UyogaMA,ZimmermannMB.IronFortificationofFoods for Infants and Children in Low-Income Countries: Effects on the Gut Microbiome, Gut Inflammation, and Diarrhea. Nutrients. 2016;8(8).
10. PrenticeAM,DohertyCP,AbramsSA,etal.Hepcidinisthemajorpre- dictor of erythrocyte iron incorporation in anemic African children. Blood. 2012;119(8):1922-1928.
11. Weiss G, Ganz T, Goodnough LT. Anemia of inflammation. Blood. 2019;133(1):40-50.
12. TheurlI,SchrollA,NairzM,etal.Pathwaysfortheregulationofhep- cidin expression in anemia of chronic disease and iron deficiency ane- mia in vivo. Haematologica. 2011;96(12):1761-1769.
13. Stoffel NU, Lazrak M, Bellitir S, et al. The opposing effects of acute inflammation and iron deficiency anemia on serum hepcidin and iron absorption in young women. Haematologica. 2019 Jan 10. [Epub ahead of print]
14. Reinisch W, Staun M, Tandon RK, et al. A randomized, open-label, non-inferiority study of intravenous iron isomaltoside 1,000 (Monofer) compared with oral iron for treatment of anemia in IBD (PROCEED). Am J Gastroenterol. 2013;108(12):1877-1888.
15. ArmitageAE,AgblaSC,BettsM,etal.Rapidgrowthisadominantpre- dictor of hepcidin suppression and declining ferritin in Gambian infants. Haematologica. 2019;104(8):1542-1553.
16. Andrews NC. Genes determining blood cell traits. Nat Genet. 2009;41(11):1161-1162.
17. AimoneAM,BrownP,Owusu-AgyeiS,ZlotkinSH,ColeDC.Impact of iron fortification on the geospatial patterns of malaria and non- malaria infection risk among young children: a secondary spatial analy- sis of clinical trial data from Ghana. BMJ Open. 2017;7(5):e013192.
18. StoffelNU,CercamondiCI,BrittenhamG,etal.Ironabsorptionfrom oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two open-label, randomised controlled trials. Lancet Haematol. 2017;4(11):e524-e533.
The wolf of hypomethylating agent failure: what comes next?
Anne Sophie Kubasch1,2,3 and Uwe Platzbecker1,2,3
1Medical Clinic and Policlinic 1, Hematology and Cellular Therapy, Leipzig University Hospital, Germany; 2German MDS Study Group (G-MDS) and 3European Myelodysplastic Syndromes Cooperative Group (EMSCO group, www.emsco.eu)
E-mail: UWE PLATZBECKER - uwe.platzbecker@medizin.uni-leipzig.de doi:10.3324/haematol.2019.222794
Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal hematopoi- etic stem/progenitor cell (HSPC) disorders main- ly affecting the elderly population.1 Hypomethylating agents (HMA) like azacitidine and decitabine have become the standard of care in elderly patients with high- risk (HR) MDS or AML unfit for intensive treatment approaches. Until today, responses to HMA have occured in less than 50% of patients and are not durable, with only a few patients achieving long-lasting remissions.2,3 Prognostic clinical markers, such as presence of peripher- al blasts, high transfusion burden, and poor performance status, have been identified as indicators of a worse out- come of HMA-based therapy.1,4 Moreover, responses to HMA are especially short-lived in patients with adverse
risk cytogenetic abnormalities compared to those with normal karyotype.1
Craddock et al. evaluated the impact of mutational pro- file on clinical response to azacitidine by analyzing 250 patients with newly diagnosed, relapsed, or refractory AML or HR-MDS. Lower complete response (CR) rates occurred in patients with an IDH2 and STAG2 mutation, higher CR rates in patients with NPM1 mutation. Mutations in CDKN2A, IDH1, TP53, NPM1, and FLT3- ITD were associated with a worse overall survival (OS) in univariate analysis, while multivariate analysis showed a decrease in OS in patients with CDKN2A, IDH1, or TP53 mutations. Moreover, ASXL1 and ETV6 were associated with short response duration after azacitidine treatment.5
Despite all efforts to try to select patients based on
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