Prevalence and Distribution of Iron Overload in Patients with Transfusion-dependent Anemias Differs across Geographic

Regions: Results from the CORDELIA Study

Yesim Aydinok,1 John B Porter,2 Antonio Piga,3 Mohsen Elalfy,4 Amal El-Beshlawy,5

Yurdanur Kilinç,6 Vip Viprakasit,7 Akif Yesilipek,8 Dany Habr,9 Erhard Quebe-

Fehling10 and Dudley J Pennell11

1Ege University Hospital, Izmir, Turkey; 2University College London, London, UK; 3University of Turin, Turin, Italy; 4Ain Shams University, Cairo, Egypt; 5Cairo

University, Cairo, Egypt; 6Cukurova University Medical Faculty, Adana, Turkey; 7Siriraj Hospital, Mahidol University, Bangkok, Thailand; 8Akdeniz University,

Antalya, Turkey; 9Novartis Pharmaceuticals, East Hanover, NJ, USA; 10Novartis

Pharma AG, Basel, Switzerland; 11 NIHR Cardiovascular Biomedical Research Unit,

Royal Brompton Hospital, London, UK

Short title: Iron Burden in Transfusion-dependant Anemias (40 characters)

Word count: 4144 Figures/Tables: 2 figures/6 tables

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AbstractObjectives: The randomized comparison of deferasirox to deferoxamine for cardiac

iron removal in patients with transfusion-dependent anemias (CORDELIA) gave the

opportunity to assess relative prevalence and body distribution of iron overload in

screened patients.

Methods: Patients aged ≥10 years with transfusion-dependent anemias from 11

countries were screened. Data were summarized descriptively, overall and across

regions.

Results: Among 925 patients (99.1% with β thalassemia major; 98.5% receiving prior

chelation; mean age 19.2 years), 36.7% had cardiac iron overload (cardiac T2*

≤20ms), 12.1% had low left ventricular ejection fraction. LIC (mean 25.8 mg Fe/g dw)

and serum ferritin (median 3702 ng/mL) were high. Fewer patients in the Middle East

(ME; 28.5%) had cardiac T2* ≤20ms versus patients in the West (45.9%) and Far

East (FE, 40.9%). Patients in the West had highest cardiac iron burden, but lowest

LIC (26.9% with LIC <7mg Fe/g dw) and serum ferritin. Among patients with normal

cardiac iron, a higher proportion of patients from the ME and FE had LIC ≥15 than

<7mg Fe/g dw (ME, 56.7 vs 17.2%; FE, 78.6 vs 7.8%, respectively), a trend which

was less evident in the West (44.6 vs 33.9%, respectively). Transfusion and

chelation practices differed between regions.

Conclusions: Evidence of substantial cardiac and liver iron burden across regions

revealed a need for optimization of effective, convenient iron chelation regimens.

Significant regional variation exists in cardiac and liver iron loading that are not well

explained; improved understanding of factors contributing to differences in body iron

distribution may be of clinical benefit.

Word count: 250 (max 250)

Key words: Thalassemia; heart; liver; iron; prevalence; distribution

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IntroductionIron-induced cardiomyopathy has long been recognized as a leading cause of death

in patients with transfusion-dependent anemias (1-4). However, liver iron

concentration (LIC) and serum ferritin, both established markers of liver iron

overload, may not reliably reflect the presence of myocardial iron deposition (5, 6).

Prompted by such observations, the development of reliable non-invasive techniques

has facilitated investigation of myocardial iron burden in the setting of transfusion-

related iron overload in clinical practice. Cardiovascular magnetic resonance (CMR),

which provides an estimate of myocardial iron load through the measurement of

cardiac T2*, has been validated and recently calibrated (5, 7). A cardiac T2* value

<20 ms indicates clinically significant cardiac iron above the normal limit which is

associated with an increased risk of impaired ventricular function, with T2* <10 ms

(ie severe cardiac iron overload) being associated with the highest risk of heart

failure (8-10). Advances in the ability to measure myocardial T2* for the

management of cardiac siderosis (10-15) (including the relationship between T2*

and heart failure (10)); a greater understanding of normal ventricular function in

thalassemia patients (16); and the availability of iron chelators with demonstrated

efficacy for the removal of cardiac iron (15, 17-22), have all contributed to the

decrease in cardiac-related mortality and morbidity over the last 10 years (23-25).

Although cardiac-related mortality continues to remain a key challenge in treating

these patients, an increasing number of deaths due to the long-term effects of iron-

induced liver toxicity are also being observed (25).

With these evolving management advances and challenges, it is important to re-

examine the prevalence of iron overload among chronically transfused patients.

Additionally, little is known about the distribution of iron burden across different

geographic regions, as few studies had sufficient sample size to enable such

assessment. CORDELIA (NCT00600938) was an international, multicenter, open-

label, randomized, Phase II clinical trial, which demonstrated the non-inferiority of

deferasirox versus deferoxamine (DFO) for the removal of cardiac iron in patients

with β thalassemia major (22). Overall, 925 patients were screened for entry into

CORDELIA. We examined the prevalence and distribution of body iron burden and in

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particular cardiac iron overload, overall and by geographic region, in this large and

representative cohort of patients with transfusion-dependent anemias.

MethodsCORDELIA was a Phase II, open-label, randomized study (NCT00600938)

conducted between April 10, 2008 and March 1, 2012 to verify the non-inferiority of

deferasirox versus DFO in cardiac iron removal (22). Patients were screened for

study entry from countries within three regions: West (Canada [n=4], Cyprus [n=10],

Italy [n=2], Turkey [n=232], UK [n=11]); Middle East (Egypt [n=387], UAE [n=45],

Lebanon [n=31]); and Far East (Taiwan [n=22], Thailand [n=122], China [n=59]).

Turkey was included in the Western region by definition of the World Health

Organization assignment to their European Region, and in order to balance patient

numbers between regions assessed here.

PatientsPatients who underwent screening for entry into CORDELIA were aged ≥10 years

with a diagnosis of β thalassemia major, Diamond–Blackfan anemia (DBA),

sideroblastic anemia or Low/Int-1 risk myelodysplastic syndromes (MDS). Patients

were also required to have a lifetime history of ≥50 red blood cell (RBC) transfusions

(predominantly leucodepleted packed red cells, but also included whole blood, non-

leucodepleted red cells or washed red cells), and to be receiving RBC transfusions

amounting to ≥10 units per year. Prior chelation or requirement for chelation therapy

was also a criterion.

Patients unable to undergo the study assessments (including magnetic resonance

imaging [MRI]) or who had psychiatric or addictive disorders that prevented them

from giving their informed consent were ineligible for screening.

Patients provided written informed consent prior to any screening assessment. The

design and protocol of the CORDELIA study were approved by the relevant Ethics

Committees at each study site. The study was conducted in accordance with the

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guidelines for Good Clinical Practice stipulated by the International Conference on

Harmonisation and Declaration of Helsinki.

Screening assessmentsAssessments were performed at screening for evaluation of myocardial siderosis

(T2*), cardiac function (as evaluated by left ventricular ejection fraction [LVEF], %),

and other iron parameters (as evaluated by LIC, mg Fe/g dry weight [dw] and serum

ferritin, ng/mL level).

Cardiac T2* and LVEF were was measured using a standardized CMR protocol for

multigradient-echo T2* acquisition (5). Briefly, 10-mm midventricular short axis slices

were acquired at nine separate echo times (5.6–17.6 ms, with 1- to 2-ms increments)

in a single breath hold. The signal intensity at each echo time was measured using

CMR tools software (Thalassemia-Tools; Cardiovascular Imaging Solutions) and an

exponential fit was used to derive the myocardial T2* in milliseconds. The resulting

images were assessed by a central CMR expert reader. LVEF was also measured

by CMR. LVEF below the lower limit of normal (LLN) was identified using Westwood

criteria, (LLN for LVEF of 59% in males and 63% in females) (16).

LIC was evaluated by measurement of the transverse relaxation parameter, R2

using a single breath-hold MRI technique that previously demonstrated high

sensitivity and specificity of R2 to liver biopsy LIC thresholds (26). Measurements

were read centrally.

Serum ferritin levels were obtained from blood samples drawn at screening and were

analyzed by a central laboratory using a validated standard kit assay.

Statistical analysisAll screened patients were included in the analysis population. Patient characteristics

were summarized by cardiac T2* categories of myocardial iron overload (<6 ms, 6–

<10 ms, 10–≤20 ms; or normal threshold >20 ms), by three geographic regions

(West, Middle East and Far East), and by splenectomy status (yes/no).

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Results are presented descriptively. For measures of iron burden, cardiac T2* is

shown as the geometric mean (anti-log of the mean of the log data) with 95%

confidence intervals (CI), while LIC and serum ferritin are recorded as mean

(standard deviation [SD]) and median (range), respectively. Data for cardiac function

(LVEF) are summarized as mean (SD).

Correlations between cardiac T2* and other iron parameters as well as age and

LVEF were assessed using Pearson’s correlation coefficient (r).

ResultsPatient characteristicsOverall, 925 patients screened for entry into CORDELIA were included in this

analysis, including patients from the West (n=259), Middle East (n=463) and Far

East (n=203) regions. The characteristics of patients are summarized in Table 1.

Table 1. Patient demographics and clinical characteristics†

Characteristic Overall(n=925)

West(n=259)

Middle East(n=463)

Far East(n=203)

Male:female, (%) 54.5:45.5 55.6:44.4 57.5:42.5 46.3:53.7

Age, years

Mean (SD) 19.2 (7.8) 19.6 (7.4) 19.3 (7.4) 18.8 (9.2)

Median

(range)

18.0

(9.0–80.0)

18.0

(10.0–49.0)

18.0

(9.0–66.0)

16.0

(9.0–80.0)

Race, n (%)

Caucasian 672 (72.6) 249 (96.1) 423 (91.4) –

Asian 251 (27.1) 10 (3.9) 38 (8.2) 203 (100)

Other 2 (0.2) – 2 (0.4) –

Weight, kg

Mean (SD) 46.6 (13.3) 49.7 (12.8) 47.0 (13.9) 41.8 (10.8)

Median (range) 47.0

(16.0–96.0)

49.9

(19.2–95.0)

47.0

(16.0–96.0)

41.8

(21.6–75.5)

Disease, n (%)

β thalassemia major 902 (99.1) 257 (99.2) 446 (99.6) 199 (98.0)

DBA 1 (0.1) 1 (0.4) – –

Low/Int-risk MDS 4 (0.4) – 1 (0.2) 3 (1.5)

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Other‡ 3 (0.3) 1 (0.4) 1 (0.2) 1 (0.5)

Splenectomy, n (%) 460 (49.7) 151 (58.3) 236 (51.0) 73 (36.0)

Hepatitis C, n (%) 101 (10.9) 14 (5.4) 76 (16.4) 11 (5.4)†Values are reported for patients with non-missing data; ‡β thalassemia intermedia, congenital

dyserythropoietic anemia, paroxysmal nocturnal hemoglobinuria (n=1 each).

DBA, Diamond–Blackfan anemia; MDS, myelodysplastic syndromes; SD, standard deviation.

Transfusion and chelation historyDespite a similar mean age, patients from the West region had received the greatest

number of transfusions (exposures to a transfusion episode) in their lifetime (median

257 [range 21–1950]), in comparison with patients from the Middle East and Far

East regions. However, the volume of blood per transfusion (median 200 mL [range

185–1400]) and the average hematocrit (median 60.0% [range 0.6–80.0]) were

lowest in the West when compared with the Middle East and Far East regions

However, the most recent transfusion policy (in the previous year) demonstrated a

shift towards more frequent transfusion exposure in patients from the Middle East

and Far East regions; in the year prior to screening, 91.4% of patients in the West

region were transfused monthly, whereas in the Middle East region, patients were

largely transfused monthly or every 2 weeks, with a similar observation in patients in

the Far East region (Table 2).

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Table 2. History of blood transfusion by geographic region

Overall West Middle East Far East

Time since start of transfusions, years

Patients, n 839 257 383 199

Mean (SD) 17.6 (7.0) 18.6 (7.1) 18.0 (6.9) 15.8 (6.7)

Median (range) 16.5 (0–49.1) 17.3 (5.1–49.1) 17.4 (0–44.1) 14.2 (2.2–38.8)

Number of transfusions episodes

Patients, n 770 248 324 198

Mean (SD) 256 (184) 315 (228) 228 (145) 229 (163)

Median (range) 216 (15–1950) 257 (21–1950) 207 (15–840) 188 (30–1000)

Volume per blood transfusion, mL

Patients, n 774 201 375 198

Mean (SD) 364 (157) 279 (170) 400 (79) 380 (212)

Median (range) 350 (148–1400) 200 (185–1400) 350 (148–700) 300 (150–1000)

Average hematocrit, %

Patients, n 620 162 324 134

Mean (SD) 63.5 (8.1) 59.2 (5.5) 64.1 (6.5) 67.3 (11.3)

Median (range) 64.0 (0.6–80.0) 60.0 (0.6–80.0) 65.0 (35.0–76.0)

65.0 (50.0–80.0)

Usual transfusion frequency in the previous year, n (%)

Patients, n 859 257 401 201

Every 2 weeks 157 (18.3) 16 (6.2) 80 (20.0) 61 (30.3)

Every month 633 (73.7) 235 (91.4) 269 (67.1) 129 (64.2)

Every 6 weeks 30 (3.5) 5 (1.9) 23 (5.7) 2 (1.0)

Every 2 months 19 (2.2) 1 (0.4) 11 (2.7) 7 (3.5)

Every 3 months 12 (1.4) – 10 (2.5) 2 (1.0)

Every 4 months 3 (0.3) – 3 (0.7) –

Every 6 months 5 (0.6) – 5 (1.2) –

Most patients (98.5%) had received previous iron chelation therapy with a range of

agents for a median of 12.3 years (0.0–37.1; Table 3). In the West region,

deferasirox was most frequently used (54.8%) just prior to study entry, compared

with 8.0% in the Middle East and 15.2% in the Far East regions. DFO was the most

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frequent last prior therapy in both the Middle East (46.4%) and Far East (36.4%)

regions. Time since initiation of chelation therapy was shortest in patients in the Far

East region (9.1 years [0.1–31.3]), indicating that these patients, who had a mean

age at screening for the study similar to patients from other regions, initiated

chelation therapy at a later age than in other regions – although these patients had

also started transfusions more recently (Table 2). Indeed, the median (range) time

difference between start of transfusions and initiation of chelation therapy was

longest in patients in the Far East region (4.8 years [‒7.0‒35.2]) compared with the

West (2.8 years [‒8.0‒27.3]) and Middle East regions (3.0 years [‒16.1‒26.0]).

Patients in the West and Far East regions had no interruption of chelation therapy

after it was initiated (median of 0 months without chelation), while for patients in the

Middle East region, the median duration of interruption was 10.0 months (0.0–600.0;

Table 3).

Table 3. Prior chelation therapy by geographic region

Overall(n=888)

West(n=259)

Middle East(n=427)

Far East(n=202)

Previous chelation, n (%) 875 (98.5) 259 (100.0) 418 (97.9) 198 (98.0)

DFO 300 (34.5) 37 (14.3) 191 (46.4) 72 (36.4)

Deferiprone 113 (13.0) 29 (11.2) 51 (12.4) 33 (16.7)

DFO + deferiprone 205 (23.6) 50 (19.3) 104 (25.2) 51 (25.8)

Deferasirox 205 (23.6) 142 (54.8) 33 (8.0) 30 (15.2)

Other† 46 (5.3) 1 (0.4) 33 (8.0) 12 (6.1)

Time since start of chelation, years

Mean (SD) 12.8 (6.7) 14.0 (7.2) 13.8 (6.1) 9.4 (5.7)

Median (range) 12.3 (0–37.1) 13.2 (0–37.1)13.4 (0.2–

34.1)9.1 (0.1–31.3)

Time without chelation after initiation, months

Mean (SD) 12.8 (38.0) 1.7 (10.9) 28.7 (54.2) 1.4 (8.6)

Median (range) 0 (0–600.0) 0 (0–108.0) 10.0 (0–600.0) 0 (0–87.0)†Unknown or patients received irregular deferiprone and/or DFO therapy.DFO, deferoxamine; SD, standard deviation.

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Cardiac iron overloadIn the overall population, geometric mean cardiac T2* was 21.8 ms (n=764; Table 4).

Overall, 36.7% of patients had cardiac iron loading with cardiac T2* ≤20 ms; 19.9%

with a cardiac T2* of 10–≤20 ms (mild-to-moderate cardiac iron), 11.4% with T2* of

6–<10 ms (severe cardiac iron) and 5.4% having T2* <6 ms (severe cardiac iron and

high risk of heart failure).

Table 4. Iron overload and cardiac function parameters in patients with transfusion-dependent anemias across geographic regions

Overall(n=925)

West(n=259)

Middle East(n=463)

Far East(n=203)

Geometric mean cardiac T2*

(95% CI), ms

21.8

(20.8, 22.9)

19.4

(17.8, 21.2)

24.5

(22.9, 26.3)

20.0

(18.0, 22.2)

Mean LVEF (SD), % 66.9 (5.8) 66.7 (5.5) 66.1 (6.1) 68.6 (5.2)

Mean LIC (SD), mg Fe/g dw 25.8 (17.1) 19.4 (14.6) 25.1 (16.5) 35.1 (16.9)

Median serum ferritin(range), ng/mL

3702(64–23,640)

2316(334–11,682)

3742(64–16,736)

5261(685–23,640)

CI, confidence interval; LIC, liver iron concentration; LVEF, left ventricular ejection fraction; SD,

standard deviation.

Geometric mean cardiac T2* differed across geographic regions, with the highest

value (indicating lower cardiac iron burden) in patients from the Middle East region

(Table 4). The distribution of cardiac iron overload severity categories also varied

between geographic regions as well as in comparison with the overall population

(Figure 1). In contrast to patients in the West (45.9%) and the Far East (40.9%)

regions, fewer patients in the Middle East regions had cardiac iron loading with T2*

≤20 ms (28.5%).

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Figure 1. Prevalence of A) cardiac and B) liver iron overload in patients with transfusion-dependent anemias across geographic regions

5.4 5.6 4.5 6.811.4 15.0

7.913.6

19.925.3

16.120.5

63.454.1

71.559.1

0102030405060708090

100

Overall (n=764)

West (n=233)

Middle East (n=355)

Far East (n=176)

T2* <6ms T2* 6–<10msT2* 10–≤20ms T2* >20ms

64.151.2

63.482.0

19.4

21.9

22.6

10.616.4

26.914.0 7.4

0102030405060708090

100

Overall (n=767)

West (n=242)

Middle East (n=336)

Far East (n=189)

LIC ≥15 mg Fe/g dw LIC 7–<15 mg Fe/g dwLIC <7 mg Fe/g dw

Pat

ient

s(%

)

A B

Geometric mean cardiac T2* also differed by splenectomy status, with a slightly

higher value in non-splenectomized patients versus splenectomized patients (23.2

ms [95% CI 21.7, 24.7] vs 20.6 ms [19.2, 22.1], respectively). More non-

splenectomized patients had cardiac T2* >20 ms (67.7 vs 59.3% of splenectomized

patients), and 12.5% of non-splenectomized patients had severe cardiac siderosis

compared with 20.7% of splenectomized patients.

Cardiac functionThere were no differences across geographic regions in mean LVEF, which was in

the normal range among all patient populations (Table 4). Among T2* categories,

mean (SD) LVEF was lowest in patients with severe cardiac iron overload

(T2* 6–<10 ms: 63.8% [6.2%]; T2* <6 ms: 63.8% [6.1%]), compared with those

patients having mild-to-moderate (T2* 10–≤20 ms: 66.4% [6.4%]) or no significant

cardiac iron overload (>20 ms: 67.9% [5.2%]).

As shown in Figure 2, 24.4% of patients with T2* <6 ms had an LVEF below the LLN

(59% [males] or 63% [females]), compared with 8.2% of patients with cardiac T2*

>20 ms and 12.1% overall.

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Figure 2. Prevalence of abnormal cardiac function across the T2* categories in patients with transfusion-dependent anemias

12.1

8.2

15.1

22.124.4

0

5

10

15

20

25

30

Overall (n=754)

T2* >20 ms (n=475)

T2* 10-≤20 ms (n=152)

T2* 6-<10 ms (n=86)

T2* <6 ms (n=41)

Pat

ient

s w

ith L

VE

F <L

LN, %

†Westwood criteria (males <59%; females <63%) (16)LLN, lower limit of normal

Other iron parametersLIC

Mean (SD) LIC was severely elevated in the overall population of screened patients

(25.8 [17.1] mg Fe/g dw) and when analyzed by geographic region (Table 4).

However, the magnitude of mean LIC elevations differed according to region, with

the lowest and highest LIC values observed in the West and Far East regions,

respectively (Table 4).

The proportions of patients meeting predefined categories of LIC severity (<7,

7–<15 and ≥15 mg Fe/g dw) are shown by geographic region in Figure 1. Overall,

64.1% of patients had severe liver iron burden, as shown by LIC ≥15 mg Fe/g dw.

The distribution of patients across categories of LIC severity varied between the

West, Far East and Middle East regions. The overwhelming majority (82.0%) of

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patients in the Far East region had LIC ≥15 mg Fe/g dw compared with

approximately half (51.2%) of patients from the West region and 63.4% from the

Middle East region (Figure 1). The proportion of patients with low liver iron burden

(LIC <7 mg Fe/g dw) was more than three-fold higher in the West region than in the

Far East region (Figure 1).

Distribution of cardiac and liver iron burden

We also examined the pattern of cardiac and liver iron distribution among screened

patients with data available for both assessments. Only four patients (all from the

West region) had severe cardiac iron burden but low LIC (T2* <10 ms and LIC

<7 mg Fe/g dw). Among patients with normal cardiac iron (T2* >20 ms), more than

half (58.5%) had an LIC ≥15 mg Fe/g dw, while 19.6 and 21.9% had LIC <7 or

7–<15 mg Fe/g dw, respectively. Within regions, a higher proportion of patients with

T2* >20 ms from the Middle East and Far East region had severe liver iron burden

(LIC ≥15 mg Fe/g dw) compared with those having LIC <7 mg Fe/g dw (Middle East

region, 56.7 vs 17.2%; Far East region, 78.6 vs 7.8%, respectively; Table 5). This

within-region trend for differences in liver iron loading among patients with normal

cardiac iron was less evident among patients from the West region (44.6% had LIC

≥15 mg Fe/g dw vs 33.9% with LIC <7 mg Fe/g dw).

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Table 5. Distribution of cardiac and liver iron overload across geographic regions in patients with transfusion-dependent anemias

CategoryGeographic regions n (%)†

West Middle East Far East

Cardiac T2* >20 ms n=121 n=215 n=103

LIC, mg Fe/g dw

<7

7–<15

≥15

41 (33.9)

26 (21.5)

54 (44.6)

37 (17.2)

56 (26.0)

122 (56.7)

8 (7.8)

14 (13.6)

81 (78.6)

LIC ≥15 mg Fe/g dw n=116 n=195 n=144

Cardiac T2*, ms

>20

10–≤20

6–<10

<6

54 (46.6)

28 (24.1)

22 (19.0)

12 (10.3)

122 (62.6)

38 (19.5)

24 (12.3)

11 (5.6)

81 (56.3)

29 (20.1)

22 (15.3)

12 (8.3)†Totals are calculated by region; values are reported for patients with non-missing data for both

LIC and T2*.

In the overall population of patients with severe liver iron burden (LIC

≥15 mg Fe/g dw; n=455), 56.5% had a cardiac T2* >20 ms. Analysis by geographic

region of cardiac T2* categories in patients with LIC ≥15 mg Fe/g dw revealed a

relatively higher proportion of patients from the Middle East region with a T2* >20 ms

than from the Far East or West regions (Table 5). The distribution of severely liver

iron-overloaded patients among the remaining mild-to-moderate (T2* 10–≤20 ms) or

severe categories (T2* <6 or 6–<10 ms) of cardiac iron burden was generally

comparable (Table 5).

Serum ferritin

Median (range) serum ferritin level was 3702 (64–23,640) ng/mL overall. Across

regions, median serum ferritin level was lower in patients in the West region than

their counterparts in the Far East region (Table 2). Correspondingly, markedly fewer

patients in the West region (47.3%) recorded serum ferritin concentrations exceeding

2500 ng/mL compared with patients from the Middle East and Far East region

(Table 6).

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Table 6. Comparison of the prevalence of iron overload, measured by serum ferritin, across geographic regions in patients with transfusion-dependent anemias

Geographic regions n (%)†

West Middle East Far East

Serum ferritin, ng/mL n=256 n=452 n=201

≤1000

1000–≤2500

>2500

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101 (39.5)

121 (47.3)

26 (5.8)

116 (25.7)

310 (68.6)

3 (1.5)

27 (13.4)

171 (85.1)†Totals are calculated by region; values are reported for patients with non-missing data.

Correlation analysesWeak correlations were observed between cardiac T2* and age (r=–0.053),

LIC (r=–0.224), serum ferritin (r=–0.258) and LVEF (r=0.183).

DiscussionAlthough cardiac-related mortality remains a leading cause of death in patients with

transfusion-dependent anemias, changing management strategies have brought

about a reduction in the number of deaths attributed to iron-induced cardiomyopathy

(23-25). Since there is a lack of awareness of the impact of these changes on the

prevalence of cardiac iron, the CORDELIA study (a randomized comparison of

deferasirox versus DFO) provided the opportunity to investigate the prevalence of

cardiac iron overload from a broader geographical perspective, as well as body iron

burden overall.

We found that approximately one-third of patients screened for entry to CORDELIA

had significant cardiac iron loading, and that the prevalence of severe cardiac

siderosis (T2* <10 ms) was 16.8%. The overall prevalence of cardiac iron overload

(T2* ≤20 ms) was of 36.7% observed in this analysis (36.7%) is slightly lower than

previous observations (27-29). A recent survey undertaken in 35 worldwide centers

among 3445 patients with β thalassemia major identified a cardiac iron overload

prevalence of 42.3% (29). Similar observations have also been reported in other

studies (27, 28). Patients screened for CORDELIA had very high liver iron burden

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overall, with a mean LIC of 25.8 mg Fe/g dw and 64.1% of patients having an LIC

>15 mg Fe/g dw. Serum ferritin levels were also elevated, with a median of 3702

ng/mL. Most patients screened for CORDELIA fell into the category for severe liver

iron burden (LIC >15 mg Fe/g dw), but with cardiac T2* in the normal range (>20

ms). However, we observed several differences in the distribution of iron overload

among patients across the regions from the West, Middle East and Far East regions,

and this may have had an impact on the observations made. Patients in the West

region had the highest cardiac iron burden, but the lowest liver iron burden and

serum ferritin levels. Cardiac iron burden was lowest in the Middle East region,

although the large majority of these patients with T2* in the normal range (>20 ms)

also had severely elevated LIC, a trend which was observed least often in patients

from the West region. Patients in the West and Middle Eastern regions were of a

similar age and had a similar duration since initiation of transfusions, so these factors

were unlikely to have significant impact on the differences in body iron distribution

across these groups. El-Beshlawy et al (2013) have also recently reported similar

observations in that in Middle Eastern patients, the prevalence of cardiac iron

loading was low despite severe liver iron burden (30). Finally, the proportion of

patients with T2* ≤20 ms reported in the Middle East region here (28.5%) contrasts

with data reported in 2009 among 81 patients from Oman, where 46% of patients

had abnormal cardiac T2* (27). Genetic differences in the thalassemia genotype or

other modifying genetic influences are unlikely to explain this difference, why Oman

has a higher proportion of patients with low T2* than other countries in the region.

These differences in prevalence but may reflect the smaller patient population in the

Omani study, but could also follow on from differences in patient management of

these patients among various Middle Eastern countries.

Age at starting transfusion or chelation therapy, the nature of transfusion or chelation

regimens and patient age at screening may all contribute to iron accumulation and

distribution. and requires further systematic investigation. Information on transfusion

and chelation practices was collected at screening, and examined in an attempt to

understand any potential impact on the observed regional differences. It is well

known that inefficient blood supply and/or difficulty in patient access leads to a lower

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frequency of transfusion in some countries (31). The large majority of patients in the

West region were transfused monthly. Approximately two-thirds of patient in the

Middle East and Far East regions also received monthly transfusions, but a

significant proportion received transfusions every 2 weeks instead. Importantly, both

the volume of blood per transfusion and the hematocrit were typically higher in

patients from the Middle East and Far East regions as well, which could have

implications on the iron loading rate (32). Furthermore, the majority of patients from

the Far East region were not splenectomized. If hypersplenism was present in these

patients, perhaps as a result of inadequate transfusion policies in the past, it could

explain the observed higher transfusion frequency in the year prior to screening and

volume per blood transfusion compared with Western patients, and could also

contribute to the higher body iron burden despite lower transfusion chronicity. Later

onset of transfusion dependency in patients from the Far East region (despite being

of a similar mean age at screening compared to patients from the other regions) may

explain the shorter exposure to prior chelation therapy. It is possible that some

patients from this region were non-transfusion-dependent thalassemia (NTDT)

patients who later became regularly transfused; a scenario which is quite common in

patients with HbE/β thalassemia in the Far East. This could also help clarify why the

highest liver iron burden was seen in this group. Serum ferritin levels in patients with

NTDT tend to underestimate liver iron burden (33-35), unless patients are initiated

on a regular transfusion program as their disease severity worsens. Thus, in these

patients serum ferritin assessments alone may not have reflected body iron burden

until later in their lives once significant liver iron deposition had already developed.

Finally, Pre-transfusional hemoglobin levels were not available in the data collected,

as this would give further insight into the local transfusion practices and the

implications on iron loading and distribution.

With regard to the last prior iron chelation therapy at screening, information on

adherence was not systematically collected. Although information on adherence was

not systematically collected, deferasirox was reported as last prior chelation in over

half of patients in the West region, but only a small proportion of patients in the

Middle and Far East regions. In these latter regions, DFO use was most common,

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perhaps due to limited patient access to oral therapies. A recent longitudinal analysis

highlighted differences between cardiac and liver iron changes depending on the

type of chelation regimen utilized, suggesting that chelation therapy should ideally be

tailored based on individual patient body iron burden (36).

Since the spleen may have a role in iron regulation (28, 37), differences in

splenectomy practices may also influence the disparity in body iron distribution

across the regions examined. A greater proportion of patients from the West region

had undergone splenectomy (58.3 vs 51.0 and 36.0% of patients from the Middle

East and Far East regions, respectively), which could contribute to the higher cardiac

iron burden in these patients as splenectomy has been implicated in increased

cardiac siderosis. A role for splenectomy in increased cardiac siderosis has been

suggested (28), where the intact spleen acts as a reservoir of excess iron, providing

a possible non-transferrin-bound iron scavenging function; hence, in the absence of

the spleen, there is less control over body iron in general (38). However, multiple

confounding factors could also contribute to this observation, such as local

transfusion practices and attitude to the safety of splenectomy. and particularly since

splenectomy is often considered in more severe disease.

Furthermore, the kinetics of iron accumulation may differ across geographic regions

depending on the genetic background of patients and may play an underlying role in

the observed differences in both the extent and pattern of iron burden between the

regions (39-42). For example, the genetic basis for hereditary and non-hereditary

iron overload in sub-Saharan Africans has been localized to a common mutation

within the ferroportin 1 (SLC40A1) gene, which is not present in Caucasians with

normal or abnormal iron load. Such genetic factors, among others, may play an

underlying role in the observed differences in both the extent and pattern of iron

burden between the regions examined here.

There was no clinically meaningful correlation between cardiac T2* and age, LIC,

serum ferritin or LVEF in this analysis, of 925 screened patients with transfusion-

dependent anemias. These findings are also which is consistent with previous

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observations (6, 43), including an earlier study in 652 patients with β thalassemia

major, which concluded that among the relationships between cardiac T2*, liver T2*

and serum ferritin, only the relationship between liver iron and serum ferritin

remained clinically meaningful (10). In particular, even though LIC was severely

elevated in the majority of patients, this parameter was not a reliable predictor of

cardiac iron loading, consistent with a disparity in the kinetics of iron accumulation

and removal between these organs (5, 44). Nevertheless, high LIC may be relevant

however because since preliminary data suggest that there may be an association

between LIC and the rate of cardiac iron removal in patients treated with deferasirox

(22, 45). Additionally, although a strong relationship between LVEF and cardiac T2*

was not shown in this analysis – likely related to the substantial number of patients

with cardiac T2* in the normal range (5) – we did observe that nearly one-quarter of

patients with very severe cardiac iron loading (T2* <6 ms) had cardiac dysfunction as

observed by LVEF below the LLN for thalassemic patients. There was also a trend

for a greater proportion of cardiac dysfunction at lower cardiac T2* categories. Kirk et

al (2009) (10) provided convincing evidence to support a relationship between the

severity of myocardial siderosis (T2* <20 ms) and the risk of heart failure or

arrhythmias, thus supporting the validity of cardiac T2* as an early predictor of heart

complications. Interestingly, however, in our study, 8% of patients with normal

cardiac T2* had abnormal LVEF, highlighting the importance of monitoring both

cardiac iron burden and cardiac function.

Despite the majority of patients having documented receipt of some prior iron

chelation therapy, total body iron burden in this large cohort was severe, indicating

that compliance and/or dosage may have been sub-optimal. Liver iron burden in

particular was severely elevated, providing evidence to support recent observations

that liver complications are on the rise, relative to heart complications (25, 46). After

heart failure, liver disorders were the second most common cause of death among

thalassemia patients in a Greek hemoglobinopathy registry study, accounting for

18% of deaths in thalassemia patients, and an increase in the number of deaths

attributed to liver complications has been observed in the last decade (25). The fact

that a significant proportion of patients continue to show cardiac iron loading, as well

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as the substantial liver iron burden demonstrates that there remains a need for the

optimization of effective and convenient iron chelation treatment regimens. This can

be achieved through more head-to-head comparisons of various chelation strategies

to help identify which patients will benefit most from the available chelation regimens.

Findings from the CORDELIA study, the first randomized trial to compare deferasirox

to DFO for the removal of cardiac iron, confirmed the non-inferiority of deferasirox,

with a trend for superiority (22). Although the combination of deferiprone and DFO is

not indicated in the product labels, randomized controlled trial data also supports the

benefit of this regimen in patients with significant cardiac siderosis (19). As removal

of iron from the heart occurs more slowly than for the liver (5, 44), longer study

durations are valuable to help gauge the true efficacy of chelation treatments.

As with studies of a non-interventional design, the potential influence of patient

selection bias for screening should be a consideration when interpreting these

results from this study. CORDELIA entry criteria were stringent with regard to body

iron burden and transfusion dependence, and physicians may have been mindful of

these when identifying patients who were appropriate for screening for a study on

cardiac iron overload, possibly selecting those patients most likely to have cardiac

iron. Additionally, a high number of patients screened for entry originated from the

Middle East region (463 of 925 patients). Observations of a lower prevalence of

cardiac iron burden in these patients may have impacted the findings of the results

reported here. Local country transfusion and chelation practices may influence

regional observations, particularly when groups were unbalanced such as the large

number of patients from Turkey compared with other countries in the West region.

Finally, cross-sectional analyses such as these should be interpreted with caution,

particularly since differences in previous chelation practices and patient compliance

are likely to impact on iron chelation efficacy and the relationship between heart and

liver iron unloading (36). It should also be noted that the results from this exploratory

analysis are presented descriptively, as the study was neither designed nor powered

to detect statistical differences between different populations.

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In summary In these patients with transfusion-dependent anemias screened for entry

into the CORDELIA study, cardiac siderosis was observed in approximately one-third

of patients screened for entry into the CORDELIA study. The burden of liver iron

loading in particular was severe in the majority of patients, despite prior chelation

therapy in almost all patients examined. We observed differences in the pattern of

iron accumulation across geographic regions examined, which may be the result of

patient age, transfusion, chelation and other disease management practices, as well

as inherent population differences; further investigation into these differences is

warranted. Collectively, these results suggest a need to optimize effective and

convenient chelation regimens for personalized treatment to better manage both

cardiac and liver burden in patients with transfusion-dependent anemias.

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AcknowledgementsWe thank Debbi Gorman of Mudskipper Bioscience Ltd for medical editorial

assistance. Financial support for medical editorial assistance was provided by

Novartis Pharmaceuticals.

Funding sourceThe study was sponsored by Novartis Pharma AG and designed by the sponsor in

close collaboration with the Study Steering Committee. The sponsor conducted the

statistical analysis. Authors had full access to the data, and participated actively in

interpreting data and critically reviewing the article with the assistance of a medical

writer funded by the sponsor. All authors approved the final manuscript.

Authorship contributionsAE-B, AY, JBP, ME, VV, YA and YK served as investigators on this trial, screening

patients. They contributed to data interpretation, reviewed and provided their

comments on this manuscript. AP, DJP, JBP, and YA served as Study Steering

Committee members overseeing the conduct of the trial, from study design to

analysis plan and data interpretation. DH assisted in developing the trial protocol,

coordinating the execution of the trial and contributing to the analysis, interpretation

and reporting of the study data. EQF served as the study analysis statistician. All

authors approved the final manuscript.

DisclosuresYA reports participation in advisory boards consultancy and speaker’s bureau, and

receiving honoraria and research grant funding from Novartis Pharmaceuticals; and

participation in advisory boards consultancy and receiving research grant funding

from Shire. JBP reports consultancy, receiving research grant funding and honoraria

from Novartis Pharmaceuticals; consultancy and receiving research grant funding

from Shire; and consultancy for Celgene. AP reports participation in advisory boards

and receiving research grant funding from Novartis Pharmaceuticals, ApoPharma

and Shire. VV received research grant support, consultation and lecture fees from

Novartis Pharmaceuticals, Government Pharmaceutical Organization (GPO)

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Thailand and Shire. DH is an employee of Novartis Pharmaceuticals, and EQF is an

employee of Novartis Pharma AG. AE-B, AY, YK, and ME have no relevant conflicts

of interest to disclose. DJP reports consultancy and receiving research grant funding

and honoraria from Novartis Pharmaceuticals and AMAG; lecture fees from Novartis

Pharmaceuticals; consultancy and honoraria from ApoPharma Inc and from Shire;

and is a director and equity holder in Cardiovascular Imaging Solutions.

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