transfusion - dependent -thalassemia major ( -tm ) is a type of inherited blood disorder resulting in severe and chronic anemia .
multi blood transfusion regimen is the first effective measure in prolonging life among these patients ; however , excessive iron overload caused by repeated blood transfusions can result in multi - organ failure .
for this reason , iron chelation therapy is vital for -tm patients with iron overload .
currently , three main iron chelators are available for clinical use : deferoxamine ( dfo ) , deferiprone ( dfp ) , and deferasirox ( dfx ) .
dfo was the first iron chelator introduced in the 60s to treat iron overload ; it is to be used as a continuous subcutaneous or intravenous solution , while dfp is an oral iron chelator .
imported brands of dfo and dfx are available in iran , and all three - iron chelators are made by iranian pharmaceutical companies . in iran , dfp is made by avicenna pharmaceuticals , and dfx is made by the osvah pharmaceutical company as osveral , which has been used to successfully treat iranian patients .
the choice of medication is made together by the physician and the patient and depends on many factors , such as the degree of iron overload , the age of the patient , the cost of the medication , and tolerability of the medication .
some patients have a large amount of iron in their body , and one iron chelator , even in the maximum recommended dose , is not enough to induce a negative iron balance . in these cases ,
two iron chelators are prescribed . combination of dfo and dfp is a classic combination now and is most recommended for severe iron overload of the heart and has been tried in our center
this study was a review of the medical records of 6 patients with -tm using the combination treatment of dfx and dfp in 2016 .
patients were included if they had high serum ferritin levels or severe iron overload , as determined by magnetic resonance imagining ( mri ) t2 * values , in spite of their maximum dosages of monotherapy with dfo or dfx .
patients were excluded if they were allergic to dfx or dfp or if they did not consent to the study .
the included patients ages , genders , histories of splenectomy , iron intakes from blood transfusions , durations and doses of iron chelation therapy , and serum ferritin levels were extracted from their medical records . as almost 250 mg of iron
is contained in each prbc ( packed red blood cell ) packed , we calculated the iron intake from blood transfusions in mg / year as follows : 250  the number of units given during one year .
the patients monthly cbc ( complete blood count ) , blood urea , creatinine , aspartate aminotransferase , alanine aminotransferase , uric acid , ferritin , and 24-hour urine protein levels were measured during treatment .
the patients were asked about any of their experienced clinical side effects , including skin rashes and gastrointestinal symptoms , during their monthly visits .
patients degrees of iron overload were assessed by serial measurements of their serum ferritin levels and their mri t2 * values in the heart and liver .
the liver iron concentration ( lic ) as mg / gr / dry weight of the liver was also compared between the patients .
spss18 software was used to conduct statistical calculations , and a paired t - test was used to calculate the difference between each before - and - after pair of measurements in order to determine the means of the changes .
a total of 6 patients ( 5 males and 1 female ) with a mean age of 23.85.8 years ( ranging from 17 to 31 ) received a combination treatment of dfp and dfx .
6 patients were receiving regular blood transfusions ( 15 ml / kg of filtered packed cells ) every 3 - 4 weeks .
all patients had been treated with dfo , dfp , or dfx in the past for various lengths of time .
the demographics , clinical states , and cardiac and liver mri values of the patients are shown in tables 1 and 2 .
their serum ferritin levels were 28001900 and 34001600 ng / ml before and after treatment , respectively ( p < 0.6 ) .
their cardiac and liver mri t2 * values were 16.6915.35 vs 17.385.74 and 2.120.98 vs 3.031.51 milliseconds ( ms ) before and after treatment , respectively ( p < 0.9 and p < 0.01 , respectively ) .
there was a significant difference in lic after combination therapy with dfp and dfx ( 7.593.16 vs 5.412.22 mg / g / dry , p < 0.01 ) .
the changes in the cardiac and liver t2 * values , lic , and serum ferritin levels before and after treatment are shown in figures 1 - 4 .
one of the patients ( case 6 ) experienced a drop in his cardiac mri t2 * value after combination therapy with dfp and dfx ; however , the cardiac status of this patient was in the normal range both before and after therapy .
two patients ( 33.33% ) discontinued treatment due to neutropenia and diarrhea . currently , three patients ( 50% ) continue treatment and have not experienced any complications .
the main objective of this study was to demonstrate the effects of dfp and dfx combination treatment on cardiac and liver mri values in iron - overloaded -tm patients .
however , the change in this patient s cardiac mri t2 * value was in the normal range , and the patient did not have cardiac siderosis according to mri . although there was no significant difference between the cardiac mri t2 * values before and after treatment statistically ( p < 0.05 ) , the cardiac mri t2 * values improved after combination therapy with dfx and dfp in the majority of the patients .
further , our findings showed that the liver t2 * values and lic were improved after treatment .
in addition , patient 5 had a remarkable increase in their cardiac mri t2 * value after 10 months of dfx and dfp combination therapy .
we believe that this considerable change was caused by more compliance with the new regimen over the course of the patients first year of its use .
the doses of dfp and dfx used in our study were 53.922.2 and 29.36.8 mg / kg / day , respectively .
we utilized dfp and dfx combination therapy in various doses according to the patient s clinical situation and laboratory data .
the drugs doses used in the literature were 75 mg / kg / day for dfp and 30 mg / kg / day for dfx ) .
the use of this combination ( dfp and dfx ) was more effective to clear the heart and the liver from iron siderosis .
this is likely a result of the synergistic effects and ability of dfx and dfp to enter cells and chelate intracellular iron .
evidence on the co - administration of dfx and dfp has only been provided by a few studies .
there are some case reports on the successful combined oral chelation therapy of dfx and dfp in -tm patients .
a case study reported a 25-year - old -tm female patient who received dfx and dfp combination therapy .
then , 3 doses of dfp at 75 mg / kg / day were added to the treatment . the patient s serum ferritin levels decreased from 4200 to 1596 ng / ml after 1 year of treatment . moreover , their cardiac and liver mri - t2 * values increased from 10.3 to 15 ms and 1.7 to 6.78 ms , respectively .
a reduction of serum ferritin was observed after 8 months of combined therapy ( less than 100 ng / ml before month 8) . in our study , the patients serum ferritin levels raised in all cases expect in patient 1 .
several studies show that serum ferritin can provide information regarding the total iron store of patients ; however , the association is not very strong .
although serum ferritin is traditionally measured in all centers for this reason , mri is the most sensitive method for the appraisal of excess iron accumulation in the liver and heart of -tm patients .
we speculate that ferritin may increase following other events , such as inflammation or infection , during dfp and dfx combination therapy .
gomer et al . used dfx and dfp combination therapy in 15 -tm patients for 12 months .
the patients serum ferritin levels , urinary iron excretion , and mri t2 * values were compared before and after the intervention .
in addition , a randomized open - label trial demonstrated that dfx and dfp combination therapy improved heavily iron - overloaded -tm patients cardiac t2 * values after one year of treatment with 2 doses of dfp at 75 mg / kg / day and 1 dose of dfx at 30 mg / kg / day .
a previous study evaluated the safety and efficacy of dfp and dfx combination treatment in 36 patients with -tm with a mean age of 136.9 years .
their mean serum ferritin level dramatically decreased to 3275618 g / l after 1 year ( p < 0.001 ) .
the mean doses of dfp and dfx were 84.45.2 ( 61 - 100 mg / kg / day ) and 33.45.2 ( 20 - 40 mg / kg / day ) , respectively . of the 36 patients ,
30 experienced transient gastrointestinal complications , joint problems , increased serum transaminases and creatinine , and/or transient proteinuria .
the study found that oral combination therapy with dfp and dfx is effective for patients with a suboptimal response to monotherapy . in the study
, patients serum ferritin levels decreased after combination therapy with dfx and dfp in contrast to the results of our study .
however , the researchers did not evaluate the patients heart and liver mri values , which is the most reliable method to estimate the intracellular iron stores of these organs .
another previous work evaluated the efficacy of dfx in 407 patients with transfusion - dependent tm in 9 different centers .
the mean dose of dfx prior to treatment was 23.54.9 mg / kg , and the maximum dose was 40 mg / kg . in the study ,
a significant decrease in the mean serum ferritin level occurred after one year of dfx monotherapy .
of the participants , 148 patients ( 36.37% ) experienced at least one side effect , such as raised serum transaminase or creatinine levels .
the main causes of withdrawal included an unsatisfactory response in 24 patients ( 5.8% ) , poor compliance in 21 patients ( 5.1% ) , and adverse effects in 13 patients ( 3.1% ) .
some limitations of our study included our small number of patients included and our short study period ; a large - scale cohort study is required to confirm our findings .
more studies are also expected to define the optimal dosing , duration , safety , and cost effectiveness of dfx and dfp combination therapy in iron - overloaded patients with -tm .
combination therapy with dfx and dfp is a new regimen for -tm patients with a heavy iron overload .
our study showed that heart and liver mri t2 * values and lic were improved after combination therapy with dfx and dfp in -tm patients .
alternative therapy with dfx and dfp could be considered to alleviate cardiac and liver iron loading in these patients .
the authors conclude that , while these results are encouraging , future studies should include a larger number of participants .
 there are few papers on the combination therapy of deferiprone ( dfp ) and deferasirox ( dfx ) in iron - overloaded patients with transfusion - dependent -thalassemia major ( -tm ) . 
 a total of 6 patients with -tm ( 5 males and 1 female ) with a mean age of 23.85.8 years ( ranging from 17 to 31 ) used this treatment regimen . 
 the mean doses of dfp and dfx were 53.922.2 and 29.36.8 
 mg / kg / day , respectively . 
 the duration of treatment was 11.54.6 months . 
 their serum ferritin levels were measured to be 28001900 and 34001600 ng / ml before and after treatment , respectively ( p<0.6 ) . 
 their cardiac magnetic resonance imaging ( mri ) t2 * values were 16.6915.35 vs 17.385.74 millisecond ( ms ) before and after treatment , respectively ( p < 0.9 ) . 
 although there was no significant difference between their cardiac mri t2 * values before and after treatment statistically , the values improved after combination therapy with dfp and dfx in most of the patients . 
 liver mri t2 * values were changed from 2.120.98 to 3.031.51 ms after treatment ( p < 0.01 ) ; further , their liver t2 * values and liver iron concentration ( lic ) were improved after treatment . 
 our study found that cardiac mri t2 * values , liver mri t2 * values , and lic were improved after combination therapy with dfp and dfx in -tm patients and that dfp and dfx combination therapy could be used to alleviate cardiac and liver iron loading . 
Competing interest statement
Introduction
Materials and Methods
Results
Discussion
Conclusions