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after 4  months of epo trial ( 40,000  ui / week ) and transfusion dependence ( four red cell transfusions per month ) , azacytidine was introduced at dose of 75  mg / m / day subcutaneously 5  days monthly per 11 courses .
[ correction added on 8 may 2015 , after first online publication :  76 corrected to 
after 12  months of iron chelation therapy ( ict ) , hematological improvement ( hi ) was reached ( wbc 3600    10/l , hb 11.8  gr / dl plt 141,000    10/l ) and ferritin level decreased ( 2756  ng / ml ) .
after hi , transfusion discontinuation lasted 6  months ( from november 2012 to march 2013 ) . in this experience , such as in literature , serum ferritin levels decreased progressively over time and deferasirox was well tolerated with manageable side effects .
platelets count remained normal and ferritin level continued to decrease ( 1758  ng / ml ) . in december 2013
he presented the following parameters : wbc 3170    10/l , hb 9.2  gr / dl , plt 185,000    10/l , ferritin 1469  ng / ml . myelodysplastic syndromes ( mds ) are hematopoietic stem cell disorders characterized by ineffective hematopoiesis , peripheral cytopenias and risk of progression to acute myeloid leukemia .
several prognostic scores of disease are based on anemia and transfusion dependence 25 . the international prognostic scoring system ( ipss ) ,
commonly used to predict newly diagnosed mds , is based on cytopenias , cytogenetic feature , and marrow blasts 2 .
the world health organization ( who)-based prognostic scoring system , used at any time during the course of disease , is based on who categories , hemoglobin level and cytogenetic features 3 . a new revised international score ( ipss - r ) was validated in 2012 .
more recently md anderson mds lower risk prognostic model ( lr - pss ) based on anemia and thrombocytopenia , unfavorable cytogenetics and marrow blasts , is validated to predict the prognosis of  poor prognosis  lower risk disease 5 .
the patient ( male ) was diagnosed in march 2010 , at the age of 60 with refractory anemia ( ra ) low - risk ipss and low - risk wpss : severe anemia , normal karyotype , bone marrow blasts inferior to five percent .
laboratory features were increased ferritin levels ( 500  ng / ml ) , normal vitamin b12 and folate stores , serum erythropoietin ( epo ) level of 110  u / l . no mutations of familiar hemocromatosis gene ( hfe ) were recognized .
the initial therapeutic approach for treatment of the symptomatic anemia was erythropoietin 40,000  ui / week and supportive care .
after 4  months of epo trial and transfusion dependence ( four red cell transfusions per month ) treatment was stopped 6 . in august 2010 ,
5-azacytidine was introduced at dose of 75  mg / m / day subcutaneously 5  days monthly .
the side effect profile of the drug was manageable , the treatment was performed for 11 cycles , but no erythroid response was noted 7 .
as a consequence of ineffective erythropoiesis and blood transfusions , ferritin levels increased . in september 2011 , he started deferasirox ( icl670 ) 20  mg / kg / day .
hematological restaging confirmed ra low - risk wpss , ferritin level further increased ( 4124  ng / ml ) .
the blood cell count was : white blood cell count ( wbc ) 2040    109/l , hemoglobin ( hb ) 7.9  gr / dl , platelet count ( plt ) 64    109/l .
after 12  months of iron chelation therapy ( ict ) , hematological improvement ( hi ) was documented ( wbc 3600    109/l , hb 11.8  gr / dl plt 141,000    109/l ) and ferritin level decreased .
transfusion discontinuation lasted 6  months , from november 2012 to march 2013 . in this experience , such as in literature , transfusion independence was obtained and maintained , reduction in ferritin levels was anticipated by a decreased transfusion requirement 817 .
in addition , deferasirox was well tolerated . during the first month of therapy temporary discontinuation due to increased serum transaminases
three year of follow - up of ict did not show any auditory or ocular adverse events .
after 18  months of deferasirox , severe anemia relapsed and transfusion dependence reappeared ( four transfusions per month ) .
platelets count remained normal and ferritin levels continue to decrease ( 1758  ng / ml ) . in december 2013 , he presented the following parameters : wbc 3170    109/l , hb 9.2  gr / dl , plt 185,000    109/l , ferritin 1469  ng / ml . hematologic restaging confirmed the diagnosis of ra according to who criteria , low - risk wpss . history and physical examination such as
laboratory features did not show any significant further data ( bleeding , vitamin deficiency , hemolytic syndrome , infections or other chronic disorders ) .
this case may suggest a possible positive effect of the drug on hematopoiesis of a low - risk mds .
major erythroid and platelet responses were recognized according to the international working group ( iwg ) 2006 criteria 8 .
a possible hypothesis of the erythroid relapse may be genomic instability of mds itself plus reactive oxygen species due to iron excess consequence of ineffective erythropoiesis and blood transfusions .
another possibility may be the occurrence of additive  noxa  effect on the hemopoietic tissue or stromal cells ( fig.1 ) .
hemoglobin and serum ferritin changes before and after erythropoietin ( epo ) , azacitidine ( aza ) and deferasirox ( a ) .
platelet count and serum ferritin changes before and after erythropoietin , azacitidine and deferasirox ( b ) .
interestingly , ict was continued until the last follow - up , november 2014 , with good compliance and stable hematologic parameters : hemoglobin , platelet , and ferritin level .
treatment of mds varies according to risk group . lower serum epo ( < 500  mu / ml ) and a lower pretreatment red blood transfusion ( rbc ) requirement ( < 2 units per months )
aza is generally administered at a dose of 75  mg / m / day subcutaneously for 7  day in patients with progressing or high - risk disease . in this patient ,
category 2 according to lr - pss ( anemia , thrombocytopenia , and age ) an alternative 5-day schedule of aza was used 7 .
it seems rationale , as reviewers and guidelines suggest , an earlier introduction of ict in transfusion - dependent mds ( 2025 rbc units , serum ferritin > 1000 or > 2000  ng / ml ) in order to reduce the body iron burden and further toxicities .
it is of interest to determine factors associated with hematologic response and mechanisms of relapse .
reduction in oxidative stress has been proposed as main explanation for this improvement and alternative mechanisms may include redistribution of iron , effect on bone marrow microenvironments or on the neoplastic clone 817 .
rbc transfusion dependence is observed in higher risk mds but also contributes to iron overload in lower risk disease due to increased absorption of iron from the gut .
hecpidin , a key negative regulator of iron export from gut and macrophages , is typically suppressed in conditions such as thalassemia or ineffective erythropoiesis 18 . more recently ,
humans lack a physiological excretion mechanism for excess iron and each rbc unit contains approximately 200250  mg of elemental iron 18 .
in addition , excess iron has been shown to suppress erythropoiesis , as evidenced by decreased burst - forming units erythroid ( bfu - e ) in patients with elevated ferritin 20 .
this pathological form of nontransferrin - bound iron ( ntbi ) that take up by cells , lead to a rise in labile iron pool ( lip ) and generate reactive oxygen species ( ros ) .
it is well known that oxidative stress leads to oxidation of proteins , lipids , and dna with increased apoptosis , organ damage , and genomic instability 21,13 .
22 observed that the drug is also active nf - kb inhibitor in mds , suggesting a possible role in reducing the transcription of antiapoptotic factor that may have an effect on erythroid inefficacy .
there is evidence from retrospective studies that ict may improve overall survival ( os ) 917 . at the present time
, it is very difficult separate the prognostic impact of iron overload from the unfavorable impact of transfusion dependence as a biologic marker of bone marrow disease . regarding biochemistry parameters , transferrin saturation ( trs ) and serum ferritin
ferritin is also an acute - phase reactant and trs has a day - to - day variability 18 .
it is well recognized that red cell transfusion iron first accumulates within reticuloendothelial cell , thereafter macrophages release excess iron and organ damage occurred ( liver , heart , endocrine glands ) .
more accurate assessment of liver iron concentration ( lic ) is possible via invasive methods ( contraindicated in mds due to thrombocytopenia ) or via magnetic resonance imaging 18 .
several consensus groups have suggested guidelines on ict 2532 including parameters for initiation ( 2025 rbc units and serum ferritin > 1000 or > 2000  ng / ml ) , patient features ( life expectancy > 6  months or > 1  year and low / intermediate1 ipss ) , target serum ferritin ( < 500 or < 1000 ) .
few retrospective studies assessed organ overload in mds 917 . in addition , cardiac iron disease is reported only in a small fraction of heavily transfused mds 3335 .
therefore , in the absence of prospective clinical trial iron chelation should be tailored to individuals .
life expectancy and comorbidities ( especially renal impairment due to documented toxicity of the drug ) , accurate transfusion history and hepatitis ( which may affect the pharmacokinetics of the drug ) , serum ferritin or laboratory evidence of iron excess ( e.g. , hereditary hemocromatosis ) may represent key factors to make decisions about ict . comparing different series of patients
is difficult because of different duration of treatment or combination of iron chelation drugs , inclusion or exclusion of cases receiving other hematological modifying drugs , different decision making regarding red cell transfusion and response criteria .
principal clinical studies with deferasirox in mds patients lic , liver iron concentration ; lpi , labile plasma iron ; os , overall survival ; e / p / n , erythroid / platelet / neutrophil ; hb , hemoglobin ; ps , patients ; ict , iron chelation therapy . porter et  al . compare the response of iron chelation in mds and other anemias ( diamon - blackfan , b - thalassemia ) . similar manageable profile and efficacy were observed in different type of diseases .
furthermore , the changes in serum ferritin level correlated with change in lic suggesting the benefit of regular serum ferritin monitoring during treatment 23 .
the large 1-year epic study demonstrated that icl670 was safe and effective in reducing iron burden and lpi .
serum ferritin level decreased following 12  months of ict as confirmed more recently by angelucci et  al .
deferasirox , may represent an effective drug in lower risk mds after other treatment options . in this experience , such as in literature ,
reduction in ferritin levels was anticipated by a decreased transfusion requirement suggesting a possible positive effect of the drug on hematopoiesis .
reduction in oxidative stress may be responsible of the hematologic improvement but further possible explanation may impact on its benefit .
interestingly , major platelet response and ferritin decrease continue until the last follow - up .
toxicity and increased morbidity due to iron overload are well - recognized complications associated with hemoglobin disorders , thalassemia ( tdt ) , and sickle cell disease ( scd ) .
deferasirox is once - daily oral chelator approved by the food and drug administration and the european medicine agency for use in transfusion - dependent anemias ( tdt , scd and mds ) and nontransfusion - dependent thalassemia .
the experience with tdt is partially applicable to mds due to different pattern of tissue iron distribution , age and comorbidities , genetic instability .
furthermore , some high - risk mds patients do not survive long enough to accumulate iron organ damage 36,37 .
more biological and clinical studies are necessary to better define mechanisms of action of deferasirox and predicting factors of response 38,39 .
association of iron chelation therapy with other mds modifying drugs or support strategies may increase rates and duration of response , but accurate assessment of toxicities and a longer follow - up are mandatory due to moderate or elevate discontinuation rate ( 4080% ) , drug adverse events reported in these patients of over 60  years of age ( gastrointestinal and renal episodes mainly ) : table2 .
safety profile of deferasirox in mds studies ae , adverse events ; ps , patients ; mds , myelodysplastic syndrome ; gi , gastrointestinal ; uln , upper limit normal .
the severity of iron overload in mds is a complex entity which includes rbc units , serum ferritin level , and organ dysfunction therefore there is a clinical need for a quantitative , noninvasive tool for iron measurement in this subset of elderly and cytopenic individuals .
a prospective randomized phase iii trial , telesto , is enrolling patients to answer question of the role of deferasirox in lower risk myelodysplastic syndromes and its impact on survival .
in addition , there are interesting phase ii trials ongoing : a phase ii study of deferasirox and erythropoietin in low- and int-1-risk mds patients and aza plus icl670 and/or vitamin d in higher risk mds .
key clinical messagedeferasirox , represents an effective iron chelator drug in lower risk myelodysplastic syndromes . 
 reduction in oxidative stress is responsible of the hematologic improvement but further explanation may impact on its benefit . 
 biological and clinical studies are necessary to better define mechanisms of action , assess toxicities , and predicting factors of response .