Hemoglobin, 32 (1–2):29–34, (2008)Copyright © Informa Healthcare USA, Inc.ISSN: 0363-0269 print/1532-432X onlineDOI: 10.1080/03630260701680474

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LHEM0363-02691532-432XHemoglobin, Vol. 32, No. 1-2, Jan 2008: pp. 0–0Hemoglobin

PROCEEDINGS 16TH ICOC

Limassol, Cyprus, October 2006

EFFECTS OF COMBINED DEFERIPRONE AND DEFEROXAMINE

CHELATION THERAPY ON IRON LOAD INDICES IN b-THALASSEMIA

Combined DFO/L1 Chelation Therapy in β-ThalassemiaM. Tsironi et al.

Maria Tsironi,1,2 George Assimakopoulos,1 Katerina Polonofi,2

Kalliopi Rigaki,1 and Athanassios Aessopos2

1Thalassaemia Unit, Department of Internal Medicine, Sparta General Hospital, Sparta, Greece2First Department of Internal Medicine, University of Athens, Medical School, “Laiko” Hospital, Athens, Greece

� The benefits of combined deferoxamine (DFO) and deferiprone (L1) chelation therapy, focusingon reducing myocardial iron loading, have been widely reported. Herein, we present the efficacy ofcombined chelation and its effects on iron load indices. Five thalassemia major (TM) patients whowere undergoing chelation monotherapy with DFO were enrolled. Inclusion criteria were magneticresonance imaging (MRI) T2* values, indicating serious heart and/or liver transfusional hemosid-erosis. Combined therapy was started with the same dose of DFO and the addition of L1. The MRIT2* studies were repeated 18 months later. An Echo-Doppler study was performed in order to fur-ther evaluate the left ventricular (LV) systolic function. Within the 18 months’ follow-up period,there was a significant statical decrease in mean serum ferritin levels. All patients increased theirMRI T2* liver values, while two patients with very low MRI T2* also increased their myocardialvalues. The MRI ejection fraction (EF) and Echo-Doppler study measurements confirmed theimprovement of systolic function. No adverse effects were reported. Combined L1 and DFO therapyseems to be effective in reducing iron excess in organ iron overloaded thalassemic patients. Magneticresonance imaging can accurately quantify iron load, while echocardiography remains a reliablemonitoring technology.

Keywords Thalassemia, Chelation, Deferoxamine (DFO), Deferiprone (L1)

Presented at the 16th International Conference on Chelation, Limassol, Cyprus, October 25–31, 2006.Address correspondence to Dr. Maria Tsironi, First Department of Internal Medicine, Laiko Hospital,

17 Aghiou Thoma St, Athens 115 27, Greece; Tel./Fax: +30-210-777-1161; E-mail: gpoyl@ otenet.gr.

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INTRODUCTION

Regular transfusion and chelation therapy with deferoxamine (DFO),applied gradually in thalassemia patients over the past decades, has led to animpressive amelioration of patients’ clinical presentation, and hasdramatically improved their life expectancy, which, according to recentstatistics, reached 68% at age 35 in Italy (1). However, despite good compli-ance to the DFO treatment, there are thalassemia major (TM) patients whodevelop complications, and heart involvement still represents the leadingcause of mortality for this population (2,3). Standard DFO therapy does notseem to be completely effective in preventing heart disease and currently,improved chelation strategies appear to be an important challenge in thetreatment of β-thalassemia (thal). Extended magnetic resonance imaging(MRI) studies have provided clinicians with an accurate quantification of tis-sue iron load (4,5) and have shown that patients with impaired left ventricular(LV) function were presenting myocardial iron overload (5–7). This has per-mitted investigators to speculate that cases with heart iron excess may be atrisk of heart dysfunction. Physicians have suggested modification of the chela-tion therapy in order to wash out excess iron, and alternative treatment strate-gies that include an increase of the dose of DFO, or a switch to oral chelatorsor to a combination of deferiprone (L1) with DFO (8–10). This study aims topresent the results of DFO plus L1 combination therapy, suggested to and fol-lowed by TM patients, selected according to the MRI iron load evaluation.

PATIENTS AND METHODS

At the Thalassaemia Unit of the Sparta General Hospital, Sparta,Greece, 28 thalassemic patients (20 with TM) were followed-up and regu-larly transfused, trying to keep a pre-transfusional hemoglobin (Hb) levelgreater than 10 g/dL. All thalassemia patients were receiving chelationtherapy with subcutaneous DFO, 30–35 mg/kg, 4–6 days a week. In follow-up,serum ferritin and hepatic function values were examined every 2 months,with annual endocrinological and cardiological follow-ups, the latterincluding echocardiogram (ECG), chest X-ray and Echo-Doppler studies.All echocardiographic and Doppler studies were carried out by the sameindividual. Audiometry and eyes examinations were performed annually.

Magnetic resonance imaging (T2* study) for the assessment of liver andheart iron load was performed for all patients at the Athens CardiovascularMagnetic Resonance (CMR) imaging site (Euromedica Encephalos),Greece. A cardiac-dedicated magnetometer (1.5 Tesla magnet-Signa CVIwith 40 mT/m gradients and appropriate cardiac software; GeneralElectric, Milwaukee, WI, USA) was used for the measurements. The leftventricular ejection fraction (LVEF) was also evaluated.

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Combined DFO/L1 Chelation Therapy in b-Thalassemia 31

In the current study, patients with severe tissue iron load as indicated bythe MRI T2* values [serious heart (T2* <14 msec.) and liver (T2* <6 msec.)siderosis] were considered for combined therapy. Five (two male and threefemale) patients were enrolled. Two patients presented both liver and heartsiderosis, while the remaining three presented serious liver siderosis values.Two other patients with severe heart iron load and clinically apparent con-gestive heart failure(CHF), under cardiological treatment, were excludedfrom this study. Combined therapy was started with DFO 35 mg/kg 5 days aweek subcutaneously for 8 to 10 hours, and the addition of L1 at a dose of70–80 mg/kg daily, divided into three doses. Elastomeric infusion pumpswere used to achieve better compliance.

A complete blood cell (CBC) count was performed every week for thefirst 2 months and on the day of transfusion for the rest of the study period,while hepatic function was monitored by transaminases levels and coagulationtests. Patients were advised to visit the hospital if fever or malaise werepresent. In cases with MRI T2* values indicative of myocardial iron load, anEcho-Doppler study and cardiological follow-up were also performed. TheMRI T2* (heart and liver) studies were repeated 18 months later.

Statistical analysis was performed using the SPSS 10.0 statistical softwarepackage (SPSS Inc., Chicago, IL, USA). Continuous variables are expressedas mean ± standard deviation (SD). A p <0.05 value was considered statisticallysignificant.

RESULTS

Demographic and laboratory data of the enrolled patients arepresented in Table 1. Combination therapy was well tolerated by all fivepatients, and no serious adverse effects such as agranulocytosis andtransaminases changes were reported.

Baseline mean serum ferritin values and SD were 2654.8 ± 1583.7 μg/L(range 437.0–4625.0 μg/L). All patients had serum ferritin valuesgreater than 1000 μg/L, with the exception of one who was enrolledbecause of an extremely low liver MRI T2* value, presenting a serumferritin value of 437.0 μg/L. In the 18 months’ follow-up, mean serumferritin values were reduced significantly to 289.4 ± 87.9 (range 161.0–387.0) μg/L (p <0.026).

With regard to tissue iron load, excess liver iron was reduced in allpatients as shown from the increased MRI T2* liver values, while twopatients, who presented very low MRI T2* myocardial values, increasedthem, reflecting a statistically significant reduction of cardiac iron(p <0.048). The MRI LVEF was improved in all the cases of heart siderosisand the Echo-Doppler study confirmed the improvement of systolicfunction.

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DISCUSSION

In TM, transfusion treatment results in the accumulation of excess ironthat exceeds the iron-carrying capacity of plasma transferrin, and causestissue iron overload that may damage vital organs such as the heart, liver,and endocrine glands (11,12). Combination of the two iron chelators (DFOplus L1) seems to maximize the chelators’ efficacy, producing additive andsynergistic effects in iron excretion. This allows a possible dose reductionand thus diminished drug toxicity (13,14), while L1 seems to be more effectivein myocardial iron removal (15).

In the current study, patients were selected for DFO plus L1 combina-tion therapy according to the organ iron overload values indicated by MRImeasurements. All patients had MRI T2* values suggesting either seriousheart (T2* <14 msec.) and/or liver (T2* <6 msec.) transfusional hemosid-erosis. Combined treatment was well-accepted by all patients with satisfac-tory results. The iron removal efficacy of the DFO/L1 combination therapywas evaluated using serum ferritin and MRI T2* values. Referring to thepatients with low MRI T2* heart values, the LVEF was decreased accordingto MRI and Echo-Doppler measurements. Low MRI T2* liver and heartvalues increased in all patients. Increase of MRI T2* heart values wasaccompanied by an increased MRI LVEF, even in cases that were withinnormal limits, before receiving the combination therapy. The echocardio-graphic LVEF values followed the same pattern, verifying further systolicfunction improvement and confirming that specific echo indices can betrustworthy in follow-up. As far as serum ferritin values were concerned,

TABLE 1 Patients’ Demographic, Personal Anamnesis and Laboratory (pre- and post-combinationtherapy) Data

Patients 1 2 3 4 5 Mean ± SD

Sex-Age M-25 M-33 F-31 F-32 F-35 31.2 ± 3.8Years on transfusion therapy 23.5 32.0 29.5 25.0 26.0 27.2 ± 3.5Years on DFO therapy 20.0 23.0 24.0 22.0 23.0 22.4 ± 1.5Serum ferritin values (pre-) (μg/L) 437.0 2114.0 2488.0 4625.0 3610.0 2654.8 ± 1583.7Serum ferritin values (post-) (μg/L) 161.0 387.0 284.0 351.0 264.0 289.4 ± 87.3a

T2* Liver (pre-) (msec.) 1.50 0.80 4.45 2.70 4.45 2.78 ± 1.67T2* Liver (post-) (msec.) 5.05 2.40 9.00 4.88 24.50 9.17 ± 8.89T2* Heart (pre-) (msec.) 31.2 7.5 33.0 24.6 6.2 20.50 ±12.85T2* Heart (post-) (msec.) 32.5 12.4 33.2 27.7 12.5 23.66 ± 10.45a

MRI LVEF (pre-) (%) 78.0 56.6 68.5 71.9 44.5 63.92 ± 13.36MRI LVEF (post-) (%) 78.07 66.63 70.14 75.60 69.00 71.89 ± 4.77Echo-Doppler LVEF (pre-) (%) 78.0 48.0 67.0 65.0 51.0 61.8 ± 12.3Echo-Doppler LVEF F (post-) (%) 79.0 65.0 69.0 71.0 64.0 69.6 ± 6.0

aPre- and post-mean paired values differences representing a statistical significance of p < 0.05.

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Combined DFO/L1 Chelation Therapy in b-Thalassemia 33

decrease after combination therapy was impressive in all five patients,although it can be used only as an indicative and not as accurate index oftissue siderosis since no strong correlation between tissue hemosiderosisand serum ferritin values was noticed, and low serum ferritin levels can bemisleading for detecting cardiac iron overload, increasing the risk ofcardiomyopathy (16).

In conclusion, we suggest that the DFO/L1 combination therapy iseffective in cases with excess tissue siderosis, as well as being safe in terms oftoxic side effects. Bearing in mind the study of Tanner et al. (17) thatrevealed myocardial siderosis, estimated as T2* values, in two-thirds of TMpatients on maintenance DFO treatment, we propose that the combinationtherapy be extended to patients with T2* heart values <20 msec., in orderfor them to achieve a negative iron balance. This safe and effective strategy,guided initially by MRI indices, would be useful to be applied according tothe clinicians’ estimation where MRI is not available, or where access is lim-ited. Furthermore, in such cases echo parameters for cardiac iron predic-tion, although of restricted value, can be used. Echocardiography has asignificant role in patient follow-up, monitoring and treatment decisionsfor prevention of iron-related cardiac pathology (18).

Since 1992, when combination of DFO and L1 was first suggested, dif-ferent therapeutic protocols were developed (19–21). In this era, the roleof the new oral chelator desferasirox has yet to be determined. The role ofL1 in myocardial chelation also needs longer studies to be well established.In the meantime, in cases of severe iron load, when maximal chelatingpotential is required, combination therapy using L1 and DFO is warrantedto reverse or avoid heart damage. This promising therapeutic option couldbe adjusted to the needs of each patient for improving iron removal andreducing chelator toxicity.

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