combination therapy of deferasirox and deferoxamine shows significant improvements in markers of...
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T R A N S F U S I O N P R A C T I C E
Combination therapy of deferasirox and deferoxamine showssignificant improvements in markers of iron overload in a patient
with b-thalassemia major and severe iron burden
Ersi Voskaridou, Veroniki Komninaka, Antonis Karavas, Evangelos Terpos, Vasilis Akianidis, and
BACKGROUND: Iron overload is a common complica-tion of patients with b-thalassemia major (TM). Despitethe availability of three iron chelators, deferoxamine(DFO), deferiprone (DFP), and deferasirox (DFX), somepatients fail to respond adequately to monotherapy withany of them. We report a case of TM who had refrac-tory severe iron overload and was successfully andsafely chelated with the combination of DFX with DFO.CASE REPORT: A 40-year-old male with b-TM, whohad been regularly transfused from the age of 2, hadbeen administered in the past iron chelation with DFO,DFP, and DFX monotherapy, without major improve-ment on his iron overload status. Liver and cardiacmagnetic resonance imaging (MRI) revealed severeiron overload, while serum ferritin was persistentlygreater than 2500 mg/L. After the patient gave informedconsent, he was administered combination therapy ofDFX at 30 mg/kg/day for 7 days per week and DFO at2500 mg/day for 4 days every week and routinely fol-lowed up for compliance.RESULTS: Eighteen months later, serum ferritin wasreduced to 680 mg/L, while both liver and cardiac MRIT2* values improved, reflecting lower iron overload. Thecombination regimen was well tolerated and no adverseevents were documented.CONCLUSION: This is the first official report of simulta-neous daily administration of the two iron chelators DFXand DFO that demonstrates the beneficial effect of thecombination on heart and liver hemosiderosis. If ourobservation is confirmed in more patients, this combina-tion could constitute a useful option in tailoring indi-vidual chelation therapy for b-TM patients with ironoverload.
Iron overload is a common complication of patientswith b-thalassemia major (b-TM) mainly resultingfrom frequent blood transfusions. Without adequateiron chelation therapy, the majority of b-TM patients
will eventually accumulate potentially fatal iron levelsleading to cardiac disease, liver disease (cirrhosis, hepato-cellular carcinoma) and endocrine abnormalities. Defer-oxamine (DFO) has been the standard of care for morethan 40 years doubling the average life span of patients,although the administration through subcutaneous infu-sions negatively affects patients compliance.1 The avail-able oral iron chelators deferiprone (DFP) and deferasirox(DFX) have shown to be effective in reducing iron burden,simultaneously improving compliance and patientsquality of life.2,3 The combination of DFP with DFO hasbeen used to increase the efficacy and induce negativeiron balance in some patients with severe iron overload.4
However, there are very limited data reported in the litera-ture regarding combination therapy of DFX with DFO. Wereport a case of b-TM who had refractory severe iron
ABBREVIATIONS: DFO = deferoxamine; DFP = deferiprone;DFX = deferasirox; LIC = liver iron concentration;MRI = magnetic resonance imaging; TM = thalassemia major.
From the Thalassaemia and Sickle Cell Disease Reference
Centre, Laikon General Hospital; the Thalassaemia Unit,
Korgialeneio Benakeio Hospital; the Department of Clinical
Therapeutics, University of Athens School of Medicine; Medical
Advisor of Novartis Hellas SACI; and the Department of
Hematology, 251 General Air Force Hospital, Athens, Greece.
Address reprint requests to: Ersi Voskaridou, MD,
Thalassaemia and Sickle Cell Disease Reference Centre, Laikon
General Hospital, 16, Sevastoupoleos Street, Ampelokipoi, 11526
Athens, Greece; e-mail: firstname.lastname@example.org.
Received for publication April 18, 2013; and accepted June
646 TRANSFUSION Volume 54, March 2014
overload and was successfully and safely chelated withthis combination.
A 40-year-old male with b-TM (IVSI-110/IVSI-110) hadbeen regularly transfused with 2 units of red blood cells(RBCs), every 30 days, from the age of 2 until the age of 20years. The transfusion rate was then increased due tomassive splenomegaly to 3 units of RBCs every 20 daysuntil the age of 25 years, when the patient had splenec-tomy. Thereafter, he has been placed on a transfusionscheme consisting of 2 units of RBCs, every 20 days. Thepatient had been administered in the past iron chelationmonotherapy with DFO or DFP but with poor compliancedue to administration issues for DFO and gastric discom-fort for DFP. He was then started on DFX monotherapy, ata dose of 20 mg/kg/day, without major improvement onhis iron overload status, even when DFX dose was esca-lated to 30 mg/kg/day, although there were concernsabout his compliance. Liver and cardiac magnetic reso-nance imaging (MRI) revealed T2* values of 0.55 and5.8 msec, respectively (both indicative of severe ironoverload; normal values of heart T2* are >20 msec). Theestimated liver iron concentration (LIC) by MRI was46.4 mg Fe/g dry weight, while serum ferritin was persis-tently greater than 2500 mg/L. MRI was performed as pre-viously described.5 It has been reported that serum ferritinvalues greater than 2500 mg/L are associated withincreased cardiac complications6 while LIC values greaterthan 15 mg Fe/g dry weight with increased risk of liverfibrosis, liver dysfunction, and premature death.7,8 Theseverity of iron overload necessitated the administrationof an intensive iron chelation regimen to which thepatient could adhere. After informed consent andapproval from the Hospital Ethics Committee wasreceived, the patient was administered combinationtherapy of DFX at 30 mg/kg/day for 7 days per week andDFO at 2500 mg/day for 4 days every week. The patientwas routinely followed up for compliance. Eighteenmonths later, serum ferritin was reduced to 680 mg/L,while both liver and cardiac MRI T2* values improved (2.5and 10.2 msec, respectively; the estimated LIC was12.3 mg Fe/g dry weight), reflecting lower iron overload(Fig 1). DFO was then discontinued due to patients will.He continued on DFX monotherapy with further improve-ment of iron overload status after 6 months. (The liver andcardiac MRI T2* were 2.4 and 12.6 msec, respectively; theestimated LIC was 10.4 mg Fe/g dry weight.) The combi-nation regimen was well tolerated and no adverse eventswere documented. Full blood count was monitored every15 days, while serum cystatin-C and serum creatininealong with proteinuria and creatinine clearance weremonitored monthly, to early identify any renal toxicity. Nodifferences from baseline values were detected (Table 1).
There was no gastrointestinal discomfort, decrease increatinine clearance, elevation of serum creatinine, orskin reactions during combined therapy.
Despite the availability of three iron chelators, somepatients fail to respond adequately to monotherapy withany of them. Combination therapy, consisting of the use ofany two chelators on the same day, has been introduced toincrease the efficacy and to induce negative iron balancein patients with severe toxic iron levels. Extensive long-term experience has shown that combined chelation withDFP and DFO rapidly reduces liver iron, serum ferritin,and myocardial siderosis; improves cardiac function;reverses and prevents endocrine complications; reducescardiac mortality; and improves survival.9,10 The combina-tion of DFX and DFO has also been used both in the pre-clinical and in the clinical setting.11-13 The clinical studieshave demonstrated that the combination of DFX and DFOinduces negative iron balance and a decrease in serumferritin but there is no information about the effect in ironconcentration in the liver or the heart. To the best of ourknowledge this is the first official report of simultaneousdaily administration of the two iron chelators DFX andDFO that demonstrates the beneficial effect of the combi-nation on heart and liver hemosiderosis, as documentedby both MRI and serum ferritin levels. Our patient wastreated with the two drugs simultaneously and this com-bination was shown to be efficacious and very safe for thispatient.
In a recent study by Grady and colleagues13 infusingDFO daily was more effective than using DFX in mostpatients, despite patient-to-patient variability. Neverthe-less, the adherence to the use of DFO is a major issue inthe management of TM patients. The reduction of chela-tion to 3 or 4 days each week could sound attractive tomany patients, but this approach would allow nontransferrin-bound iron to accumulate in the plasma whenno iron chelator is present. To avoid this situation(increased deleterious effects of nontransferrin-boundiron and LPI), DFX could be taken daily, supplementedwith DFO four times a week, like in our patient, preferablyon alternate days to minimize injection-related sideeffects, still providing continuous chelation (almost 24 hreach day). It is difficult to establish from a single case thepossible mechanism for the efficacy of this combinedregimen. It is suggested that daily use of both drugs mighthave a synergistic (like the shuttle effect of the DFX-DFPcombination) or additive effect,13 but this could only bedetermined by a randomized clinical trial. If our observa-tion is confirmed in more patients, the combination ofDFO and DFX could constitute a useful option in tailoringindividual chelation therapy for b-TM patients with ironoverload.
COMBINATION THERAPY OF DEFERASIROX AND DEFEROXAMINE
Volume 54, March 2014 TRANSFUSION 647
Fig. 1. MRI, ferritin levels, and LIC during treatment. The figure shows the rapid increase of both liver