ox in thal inter media

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Treatment with deferasirox (Exjadeâ) effectively decreases iron

burden in patients with thalassaemia intermedia: results of a

pilot study

Iron loading in thalassaemia intermedia (TI) occurs primarily

due to increased intestinal iron absorption secondary to

chronic anaemia and is further exacerbated by intermittent

blood transfusion therapy. In contrast to thalassaemia major

(TM) the evaluation of body iron based on serum ferritin

alone may underestimate the severity of iron overload in TI

(Pakbaz et al , 2007). Therefore, direct assessment of liver iron

concentration (LIC) by either biopsy or non-invasive magnetic

resonance imaging (MRI) is recommended (Jensen, 2004).Relatively few studies have evaluated the efficacy, safety and

dosing regimen of iron chelation therapy specifically in TI

(Cossu et al , 1981; Olivieri et al , 1992). Deferasirox (Exjadeâ)

is a once-daily orally administered iron chelator approved for

the treatment of transfusional iron overload in various

anaemias (Cappellini et al , 2006). The aim of this preliminary,

open-label, prospective, single-centre trial was to evaluate the

efficacy and safety of deferasirox in sporadically transfused,

iron-overloaded patients with TI.

Adult male or female patients who had received sporadic red

blood cell (RBC) transfusions (£20 RBC units in their lifetime)

and had confirmed liver or cardiac iron overload (serum

ferritin levels of ‡1000 lg/l, liver MRI T2* of <25 ms or

cardiac T2* of <28 ms) were included in this study. Patients

were excluded if they were pregnant, showed signs of hepatic

failure (transaminase levels of >500 U/l) or renal failure

(creatinine clearance <60 ml/min) or had a left ventricular

ejection fraction (LVEF) of <50%.

The starting deferasirox dose was 10 or 20 mg/kg per day

depending on baseline iron burden. Dose adjustments were

permitted after 3 months (in increments of 5 mg/kg per day every 3 months as required) based on serum ferritin trends

(rises of ‡1000 lg/l on 2 visits or >2500 lg/l without

decreasing trend) and reduced for elevated levels of creatinine,

urinary protein/creatinine ratio and transaminases, and in

response to adverse events. Patients provided written,

informed consent before entering the study. The study was

conducted in accordance with Good Clinical Practice guide-

lines and the Declaration of Helsinki.

The primary efficacy endpoint was the improvement in MRI

T2* values in the liver and the heart from baseline after

12 months of deferasirox therapy. The secondary efficacy

endpoints included evaluation of changes in serum ferritin,

Table I. Baseline haematology, liver and cardiac iron characteristics.

Patient

Age

(years)/gender

Haemoglobin

(g/l)

No. of

lifetime

transfusions

Previous chelation

therapy

Liver T2*

(ms)

Serum ferritin

(lg/l)

Heart T2*

(ms) LVEF (%)

1 43/M 123 20 None 1Æ52 1029 30Æ64 71

2 38/F 55 20 DFO non-compliant* 1Æ67 1028 44Æ84 72

3 40/M 64 18 DFO non-compliant* 3Æ76 1949 41Æ45 52




7 44/F 85 19 DFO non-compliant* 8Æ03 1386 32

Æ22 73



10 28/M 97 20 DFO allergy, DFP NM 1759 NM 65

11 39/F 72 5 None 1Æ33 1160 43Æ75 67

Mean ± SD 41Æ2 ± 6Æ5 82 ± 19 17Æ4 ± 4Æ7 – 3Æ4 ± 3Æ0 2030 ± 1340 38Æ9 ± 5Æ9 66Æ3 ± 8Æ1

Patient 1 was homozygous for haemoglobin db, which explains his high haemoglobin level; he belonged to the thalassaemia intermedia group without

almost any transfusions at all. Patient 2 was double heterozygous b0 thal/Hb Knosos and remains without transfusions at this low level as she refused

transfusions.

SD, standard deviation; DFO, deferoxamine; DFP, deferiprone; NM, value not measured.

*Sporadic use.

correspondence

ª 2009 Blackwell Publishing Ltd, British Journal of Haematology , 148, 332–340



incidence, type and severity of adverse events relating to

biochemical changes and patient disposition.

Overall, 11 patients were enrolled and completed 12 months

of deferasirox therapy. At baseline, all patients had indicators

of iron overload (Table I). Serum ferritin was >1000 lg/l in all

patients and liver MRI T2* was £6 ms in seven patients, which

is indicative of moderate-to-heavy iron overload [equivalent to

7–14 mg Fe/g dry weight (dw)] and 7–12 ms in three patients

indicative of mild overload (equivalent to 3–6 mg Fe/g dw).

Cardiac T2* was normal in all patients (T2* of >28 ms). The

majority of patients had previously received deferoxamine

although its use was sporadic due to poor compliance. Two

patients (Patients 3 and 9) received 10 and 12 units of packed

RBCs, respectively during the study due to pulmonary

hypertension, which was diagnosed after deferasirox initiation.

Nine of 11 patients started on deferasirox 10 mg/kg per day;

the remaining two patients (Patients 5 and 9) started on

20 mg/kg per day due to very high serum ferritin levels

(>4000 lg/l) and liver T2* indicating moderate-to-heavy iron

overload. By the end of the study, doses had been adjusted so

that nine patients were receiving 20 mg/kg per day and two

were receiving 30 mg/kg per day based on the experience and

knowledge derived from TM (Thalassaemia International

Federation, 2008) as there are currently no clear guidelines

for the management of iron overload in TI.

After 12 months of deferasirox therapy, liver MRI T2*

improved from baseline in 9/10 patients from a mean value of

3Æ4 ± 3Æ0 t o 4Æ4 ± 3Æ0 ms (Fig 1A, Table II); resulting in a

significant mean increase from baseline of 1Æ0 ms (P = 0Æ02).

Serum ferritin was reduced from baseline in 9/11 patients from

a mean value of 2030 ± 1340 to 1165 ± 684 lg/l (Fig 1B,

Table II). The mean reduction in serum ferritin from baseline

was significant at 865 lg/l (P = 0Æ02). LIC was evaluated based

on liver MRI T2* values according to Wood et al (2005)

(Table II). A correlation with serum ferritin was observed at

baseline (r = 0Æ63, P = 0Æ002), but there were no significant

10

(A) (B)

6000

5000

4000

3000

2000

1000

0

8

6

4

2

0BL 12

9·8

4960

4318

19701949

175915111386126011601029

1028

248466

7497609631065117812001490

2200

2500

8·5

6·6

5·3

3·2

2·9

2·3

2·01·9

1·6

0·9

1·2,1·21·31·5

1·7

3·8

6·9

7·6

8·0

Time (months)

L i v e r T 2 * ( m s )

S e r u m f e

r r i t i n ( µ g / l )

BL 12Time (months)

Fig 1. Change in liver T2* (A) and serum ferritin (B) from baseline by patient after 12 months of treatment with deferasirox. BL, baseline.

Table II. Serum ferritin level, liver MRI and

LIC at baseline and after 12 months treatment.

Patient

Age

(years)/

sex

Serum

ferritin

(lg/l)

baseline

Serum

ferritin

(lg/l) after

12 months

Liver T2*

(ms) baseline

Liver T2*

(ms) after

12 months

LIC

(mg/g dw)

baseline

LIC

(mg/g dw)

after

12 months

1 43/M 1029 1490 1Æ52 1

Æ89 16

Æ91 13

Æ64

2 38/F 1028 466 1Æ67 2Æ85 15Æ41 9Æ11

3 40/M 1949 2200 3Æ76 6Æ63 6Æ95 4Æ03

4 53/F 1970 1200 1Æ15 2Æ25 22Æ28 11Æ48

5 36/M 4318 1178 1Æ21 1Æ97 21Æ19 13Æ09

6 48/F 1511 749 7Æ64 8Æ54 3Æ52 3Æ17

7 44/F 1386 1065 8Æ03 9Æ76 3Æ36 2Æ80

8 43/M 1260 248 6Æ93 5Æ31 3Æ86 4Æ98

9 41/F 4960 2500 0Æ87 1Æ61 29Æ39 15Æ97

10 28/M 1759 963 1Æ5 – 17Æ13 –

11 39/F 1160 760 1Æ33 3Æ23 19Æ29 8Æ05

Correspondence

ª 2009 Blackwell Publishing Ltd, British Journal of Haematology , 148, 332–340 333



correlations between percentage changes of serum ferritin, LIC

or liver MRI T2* after 12 months of therapy. Mean cardiac T2*

and LVEF were normal at baseline and did not change

significantly after 12 months of deferasirox treatment; after

12 months, mean cardiac T2* was 39Æ8 ± 4Æ5 ms (+0Æ9 ms;

P = 0Æ64) and LVEF was 66Æ9 ± 7Æ9% (+0Æ6%; P = 0Æ76). These

data indicate that deferasirox was effective in reducing labora-

toryand imaging evidence of iron overload in most of these iron-

overloaded patients with TI over a period of 12 months of

treatment. In contrast to TM, where cardiac iron loading is

significant and heart disease is the main cause of death

(Brittenham et al , 1994), myocardial iron loading has not been

documented in TI (Origa et al , 2008). In agreement with these

observations, myocardial ironlevelswere normalat baseline and

remained normal during the 12-month study period.

Mean aspartate aminotransferase and alanine aminotrans-

ferase levels progressively decreased during the study from

baseline values of 64Æ8 ± 29Æ6 and 63Æ5 ± 29Æ5 U/l, respectively

to 42Æ5 ± 18Æ1 and 36Æ5 ± 17Æ6 U/l after 12 months of defer-

asirox therapy (P = 0Æ04 and P = 0

Æ02 respectively). There

were no significant changes in mean serum creatinine, cystatin-

C or 24-h proteinuria. These data indicate a concomitant

improvement in liver function with the reduction in body iron

following deferasirox therapy for 12 months.

In general, adverse events were mild and consistent with that

documented throughout the registration studies of deferasirox

(Vichinsky, 2008). Nausea was reported in eight patients

(73%) and diarrhoea was reported in two patients (18%)

within the first month of deferasirox therapy. These adverse

events were treated conventionally and did not re-occur within

the 12 months of this study.

In conclusion, deferasirox provided effective control of iron

levels in this small population of minimally transfused TI

patients with no significant adverse events. Larger trials, which

have been just started, will clearly define the efficacy and safety

of deferasirox in TI.

Acknowledgements

Financial support for medical editorial assistance was provided

by Novartis Pharmaceuticals. We thank Dr Rebecca Helson

for medical editorial assistance with this manuscript and

Mrs Marialena Konstantinidou for administrative support.

Disclosures

All authors have nothing to disclose.

Ersi Voskaridou1

Eleni Plata1

Maroussa Douskou2

Manousos Papadakis1

Eleni-Evangelia Delaki1

Dimitrios Christoulas3

Evangelos Terpos3

1Thalassaemia Centre, Laikon Hospital, Athens, 2Bioiatriki Medical

Centre, Athens, and 3Department of Medical Research,

251 General Air Force Hospital, Athens, Greece.

E-mail: [email protected]

References

Brittenham, G.M., Griffith, P.M., Nienhuis, A.W., McLaren, C.E.,

Young, N.S., Tucker, E.E., Allen, C.J., Farrell, D.E. & Harris, J.W.

(1994) Efficacy of deferoxamine in preventing complications of iron

overload in patients with thalassemia major. New England Journal of

Medicine, 331, 567–573.

Cappellini, M.D., Cohen, A., Piga, A., Bejaoui, M., Perrotta, S.,

Agaoglu, L., Aydinok, Y., Kattamis, A., Kilinc, Y., Porter, J., Capra,

M., Galanello, R., Fattoum, S., Drelichman, G., Magnano, C.,

Verissimo, M., Athanassiou-Metaxa, M., Giardina, B., Kourakli-

Symeonidis, A., Janka-Schaub, G., Coates, T., Vermylen, C., Olivieri,

N., Thuret, I., Opitz, H., Ressayre-Djaffer, C., Marks, P. & Alberti, D.

(2006) A phase 3 study of deferasirox (ICL670), a once-daily oral

iron chelator, in patients with b-thalassemia. Blood , 107, 3455–3462.

Cossu, P., Toccafondi, C., Vardeu, F., Sanna, G., Frau, F., Lobrano, R.,Cornacchia, G., Nucaro, A., Bertolino, F., Loi, A., De Virgiliis, S. &

Cao, A. (1981) Iron overload and desferrioxamine chelation therapy

in beta-thalassemia intermedia. European Journal of Pediatrics, 137,

267–271.

Jensen, P.D. (2004) Evaluation of iron overload. British Journal of

Haematology , 124, 697–711.

Olivieri, N.F., Koren, G., Matsui, D., Liu, P.P., Blendis, L., Cameron,

R., McClelland, R.A. & Templeton, D.M. (1992) Reduction of tissue

iron stores and normalization of serum ferritin during treatment

with the oral iron chelator L1 in thalassemia intermedia. Blood , 79,

2741–2748.

Origa, R., Barella, S., Argiolas, G.M., Bina, P., Agus, A. & Galanello, R.

(2008)No evidenceof cardiac iron in20 neveror minimallytransfused

patients with thalassemia intermedia. Haematologica, 93, 1095–1096.

Pakbaz, Z., Fischer, R., Fung, E., Nielsen, P., Harmatz, P. & Vichinsky,

E. (2007) Serum ferritin underestimates liver iron concentration in

transfusion independent thalassemia patients as compared to regu-

larly transfused thalassemia and sickle cell patients. Pediatric Blood

Cancer , 49, 329–332.

Thalassaemia International Federation (2008) Guidelines for the Clin-

ical Management of Thalassaemia, 2nd Revised edn. TIF edition,

Nicosia, Cyprus. Available at: //www.thalassaemia.org.cy/pdf/

Guidelines_2nd_revised_edition_EN.pdf.

Vichinsky, E. (2008) Clinical application of deferasirox: practical

patient management. American Journal of Hematology , 83, 398–

402.

Wood, J.C., Enriquez, C., Ghugre, N., Tyzka, J.M., Carson, S., Nelson,M.D. & Coates, T.D. (2005) MRI R2 and R2* mapping accurately

estimates hepatic iron concentration in transfusion-dependent

thalassemia and sickle cell disease patients. Blood , 106, 1460–1465.

Keywords: thalassaemia intermedia, iron chelation therapy,

iron overload, magnetic resonance imaging, T2*.

First published online 26 October 2009

doi:10.1111/j.1365-2141.2009.07930.x

Correspondence

334 ª 2009 Blackwell Publishing Ltd, British Journal of Haematology , 148, 332–340

ox in thal inter media

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