Int J Hematol (2014) 99:706–713 DOI 10.1007/s12185-014-1575-1
ORIGINAL ARTICLE
Cardiac T2* MRI assessment in patients with thalassaemia major and its effect on the preference of chelation therapy Arzu Akcay • Zafer Salcioglu • Kazim Oztarhan • Deniz Tugcu Gonul Aydogan • Nuray Aktay Ayaz • Helen Bornaun • Hulya Sayilan Sen • Ferhan Akici • Burhan Akdana
•
Received: 18 June 2013 / Revised: 18 March 2014 / Accepted: 18 March 2014 / Published online: 10 April 2014 Ó The Japanese Society of Hematology 2014
Abstract The aim of the study is to assess the relationship between T2* magnetic resonance imaging (MRI) values and age, serum ferritin level, left ventricular ejection fraction (LVEF), splenectomy status, and to identify appropriate modifications to chelation therapy based on T2* MRI results of children with thalassaemia major. Sixty-four patients with thalassaemia major (37 girls/27 boys) older than 8 years of age were enrolled in the study. Based on the first T2* MRI, the patients’ myocardial iron depositions were classified into three groups: T2* MRI \10 ms (high risk group), T2* MRI 10–20 ms (mediumrisk group) and T2* MRI [20 ms (low-risk group). There was no significant relationship between T2* MRI value and ages, serum ferritin levels and splenectomy status of thalassaemia major patients. The mean LVEFs were 60, 75, and 72.5 % in the high-, medium-, and low-risk groups,
respectively (P = 0.006). The mean cardiac iron concentrations calculated from the T2* MRI values were 4.96 ± 1.93, 1.65 ± 0.37, and 0.81 ± 0.27 mg/g in the high-, medium-, and low-risk groups, respectively. Chelation therapies were re-designed in 24 (37.5 %) patients according to cardiac risk as assessed by cardiac T2* MRI. In conclusion, until recently, T2* MRI has been employed to demonstrate cardiac siderosis without a direct relationship with the markers used in follow-up of patients with thalassaemia. However, modifications of chelation therapies could reliably be planned according to severity of iron load displayed by T2* MRI. Keywords Thalassaemia major T2* MRI Cardiac iron concentration Chelation therapy
Introduction All authors contributed to data collection and drafting the paper.
Electronic supplementary material The online version of this article (doi:10.1007/s12185-014-1575-1) contains supplementary material, which is available to authorized users. A. Akcay (&) Z. Salcioglu D. Tugcu G. Aydogan N. A. Ayaz H. S. Sen F. Akici Pediatric Hematology-Oncology, Department of Pediatrics, Istanbul Kanuni Sultan Suleyman Education and Research Hospital, Turgut Ozal cad No. 1, Halkali, 34306 Istanbul, Turkey e-mail:
[email protected] K. Oztarhan H. Bornaun Pediatric Cardiology, Department of Pediatrics, Istanbul Kanuni Sultan Suleyman Education and Research Hospital, Istanbul, Turkey B. Akdana Department of Radiology, Istanbul Sisli Etfal Education and Research Hospital, Istanbul, Turkey
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The purpose of the chelation therapy applied to patients with thalassaemia major (TM), who are dependent on transfusion is to prevent morbidity and early mortality associated with the toxic effects of transfusional iron accumulation [1]. Approximately 50–70 % of the patients are died by heart failure due to myocardial siderosis [2, 3]. To determine the most appropriate iron chelation therapy, the iron load of the body should be measured accurately and the cardiac risk should be assessed. Since, routinely used serum ferritin levels may be affected by many factors, it may not provide reliable information about the iron load of the body and the cardiac iron accumulation of patients with transfusion-dependent TM [1]. Evaluations such as electrocardiography and computerized tomography are inadequate to show the iron accumulation in the heart. Left ventricular ejection fraction
Cardiac T2* MRI and choice of chelation therapy
(LVEF) measurement is not a method of choice for early determination of cardiac iron accumulation as well [3]. The T2* magnetic resonance imaging (MRI) assessment, which has been used since 2000s, is a non-invasive method for imaging the iron accumulation in vital organs such as the heart, liver, pancreas, and pituitary gland. The cardiac T2* MRI assessment has gained a critical importance in the management of TM patients in terms of cardiac complications and the preference of iron chelation therapies [4, 5]. Normal T2* MRI is [20 and 40 ms on average [6]. Cardiac T2* MRI shows the severity of iron accumulation (T2* MRI \10 ms) in 90 % of TM patients with heart failure [7]. In terms of developing heart failure, patients with T2* levels \10 ms are 160 times risky than the ones with T2* levels [10 ms [4]. To achieve a goal of increasing the T2* MRI value above 20 ms, intensive chelation regimens are required to removing iron rapidly [1]. Besides being a measurement of patient’s prognosis, T2* MRI had become a guide method for preference of chelation therapies. While planning the chelation therapies, iron load of the body, the cardiac risks with the organ specific impacts and undesired effects of the chelating agents (Deferoxamine [Desferal (DFO) Novartis Pharma AG, Basel, Switzerland], Deferiprone [Ferriprox (DFP), Apotex Inc., Toronto, ON, Canada], Deferasirox [Exjade (DFX), Novartis Pharma AG, Basel, Switzerland]) should be taken into consideration. The purpose of present study is to assess the myocardial iron depositions of TM patients with T2* MRI, and also to examine the relationship between the T2* MRI values and the age, serum ferritin level, LVEF, number of transfusions and splenectomy status, and to present the changes made in chelation therapies according to T2* MRI results.
Patients and methods A total of 64 patients who were diagnosed as thalassaemia major and receiving regular erythrocyte transfusions were enrolled to the study. T2* MRI assessments of these patients were conducted between December 2008 and September 2010. For these patients, the target pretransfusion hemoglobin level is 9–10 g/dl at our clinic. The mean of serum ferritin levels (Abbott AXSYM System) of the last two visits was recorded. Echocardiography Evaluation of systolic and diastolic parameters and LVEF measurements were performed by M-mode by the same pediatric cardiologist. Two-dimensional and Doppler echocardiography (Acuson, Cypress) were performed in all patients. Measurements were performed one week after
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transfusion as recommended by the American Society of Echocardiography. Cardiovascular magnetic resonance imaging The T2* MRI assessments of our patients were conducted one week after transfusion at the Department of Radiology. The Siemens 1.5 Tesla MRI (Symphony, Siemens, Erlangen, Germany) device was used. Since, organs containing iron darken more rapidly, MRI evaluation help to detect iron load. Myocardial T2* MRI was performed with a cardiac-gated, single breath-hold, eight-echo sequence (2.6–16.7 ms) for imaging a single midventricular shortaxis slice. For each echo-time left ventricular signal, intensity was measured and analyzed. Left ventricular dimensions and function were assessed by long-axis cines and short-axis cines. T2* analysis was performed using Thalassaemia Tools (a plug-in of CMR tools, Cardiovascular Imaging Solutions, London, UK) with curve truncation to account for background noise [8]. The patients were classified as high risk in terms of cardiac complications if their T2* MRI values were \10 ms, medium risk if they were between 10-20 ms, and low risk if they were [20 ms [4, 9]. Cardiac iron concentration Cardiac T2* MRI results were employed to calculate cardiac iron concentrations with the following equation: [Fe] = 45(T2*)-1.22. In this formula, [Fe] is the cardiac iron concentration in milligrams per gram dry weight [10]. Chelation therapy Only DFO (20–60 mg/kg/day, 5 to 7 days in a week, through 8–12 h subcutaneous infusion) was used for the iron chelation therapy of patients with TM until DFP was licensed and introduced into the market in our country in 2004. Following 2004, the combination of DFO (40–60 mg/kg/day, 2–5 days in a week, through 8–12 h subcutaneous infusion) and DFP (75–100 mg/kg/day, every day, as divided in 3 doses) had begun to be used for patients older than 10 years of age or having serum ferritin levels [2500 ng/dl or with additional organ dysfunction. Following the licensed availability of DFX in our country after March 2006, four types of patients were started on DFX (20–40 mg/kg/day, single dose): (1) those whose chelation therapy just started; (2) those experiencing compliance problems with DFO monotherapy; (3) those with poor compliance to the combination therapy, (4) patients older than 10 years of age without any serious cardiac problems even though their serum ferritin values were [2500 ng/dl.
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The ages, serum ferritin values, LVEF, and additional organ dysfunction findings of the patients as well as the organ specific impacts and undesired effects of the chelating agents were taken into consideration in managing the chelation therapies of the patients before T2* MRI was used. The recommendations of the United Kingdom Thalassaemia Society [11] were taken as basis for any changes in the chelation regimen following the T2* MRI assessment. Besides the demographical data of the patients; their serum ferritin levels, LVEF values, the chelation regimens were recorded, T2* MRI values, cardiac iron concentrations, number of transfusions and splenectomy status were examined on retrospective basis. The relationship between the T2* MRI and the age, serum ferritin value, and LVEF used in the follow-up of TM patients and previous chelation therapies were examined. In addition, the changes made in the chelation therapies according to T2* MRI results were recorded. Patients with treatment modifications that were made according to adverse effects, drug compliance, and costs were excluded. Written informed consents were taken from all of the patients or their legal guardians. The institutional review board approved this study. Statistical analysis All data were analyzed using the SPSS version 16.0 statistical package. Categorical data are presented as frequency and percentage (%). Continuous variables were presented as mean ± standard deviation (SD), median, minimum and maximums. The comparisons among groups were made by Kruskal–Wallis and Mann–Whitney U tests for continuous variables with non-normal distribution and a Chi-squared test for categorical variables. Correlations of T2* MRI with LVEF, serum ferritin levels, and ages of patient were performed using the Pearson correlation test. A two-tailed P value \0.05 was considered statistically significant.
Results In the present study, 37 (54.7 %) of TM patients were girls, 27 (45.3 %) were boys, and the mean age was 15.0 ± 4.16 years (median 14, min 8, max 25). General characteristics of our patients have been summarized in Table 1. The details related to the median T2* MRI value, cardiac iron concentrations, as well as ages, serum ferritin levels, and LVEF values for these sub-groups have been given in Table 2. While the mean T2* MRI value was 20.2 ms, the T2* MRI values of 5 (8 %) patients were \10 ms, values of 36 (56 %) patients were between 10 and
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A. Akcay et al. Table 1 General characteristics of our patients Mean ± SD (minimum, maximum)
Median
Patients Gender
Female = 37 (54.7 %), Male = 27 (45.3 %)
Splenectomy
Yes = 31 (48 %), No = 33 (52 %)
Mean age ± SD (years)
15 ± 4.16 (8.4–25.6)
14
Hematology Pretransfusion hemoglobin (g/dl) Biochemical marker
9.5 ± 1.8 (8.3–11.9)
9.2
2770 ± 2046 (424–11087)
2224
LVEF (mean) (%)
73.2 ± 7.6 (41–89)
73
T2* MRI (ms)
20.2 ± 10.4 (4.2–59.7)
18
Iron concentration (mg/g)
1.58 ± 1.21 (0.31–7.81)
1.32
Ferritin (mg/dl) Cardiac parameters
LVEF left ventricular ejection fraction, MRI magnetic resonance imaging
20 ms, and the T2* MRI values of 23 (36 %) patients were [20 ms. The mean age of the patients within the group, whose T2* MRI values were \10 ms, was older compared to those of the other groups, their serum ferritin values were higher, mean LVEF values were lower and cardiac iron concentrations were higher. However, this difference of age and serum ferritin values was not statistically significant (P = 0.509 and P = 0.057). The mean LVEFs were 60, 75, and 72.5 % in the high-, medium-, and low-risk groups, respectively (P = 0.006) (Table 2). Significance was observed at group’s comparisons (for the groups with high risk and medium risk, P = 0.007; for the groups with high risk and low risk, P = 0.026; for the groups with medium risk and low risk, P = 0.044). While the mean cardiac iron concentration calculated from the T2* MRI values was 1.58 ± 1.2, the subgroup’s mean cardiac iron concentrations were 4.96 ± 1.93, 1.65 ± 0.37, and 0.81 ± 0.27 mg/g for high-, medium-, and low-risk groups, respectively (Table 2). Splenectomy was performed in 4 of 5 patients in the group with T2* MRI values \10 ms. A significant relationship was not found between T2* MRI and the splenectomy status. The mean serum ferritin values, LVEF, and the ages of the patients according to T2* MRI values are depicted in Figs. 1, 2, 3. There was no significant correlation between T2* MRI and other variables. Before the T2* MRI assessment, 33 of our patients were receiving DFO ? DFP combination therapy, 24 patients were receiving DFO, and 7 patients were receiving DFX.
Cardiac T2* MRI and choice of chelation therapy
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Table 2 The comparison of T2* MRI values regarding to age, serum ferritin levels, left ventricular ejection fraction, cardiac iron concentrations, and splenectomy status of patients with thalassemia major T2*
P
\10 ms
10–20 ms
[20 ms
n (%)
5 (% 8)
36 (% 56)
23 (% 36)
T2* (ms)
6.6 ± 2.08
15.5 ± 2.5
29.4 ± 10.8
(mean ± SD)
(min 4.2, max 9.62) median 6,7
(min 10.9, max 19.2) median:15.7
(min 20.1, max 59.7) median 25.7
Cardiac iron concentration (mg/g) (mean ± SD)
4.96 ± 1.93
1.65 ± 0.37
0.81 ± 0.27
(min 2.84, max 7.81)
(min 1.22, max 2.44)
(min 0.31, max 1.16)
median 4.41
median 1.55
median 0.85
Age (years)
17.7 ± 3.7
13.7 ± 3.7
16.2 ± 4.4
(mean ± SD)
(min 13, max 24)
(min 8.4, max 23)
(min 8.8, max 25.6)
median 16.6
median 13.6
median 15.8
299 ± 63
233 ± 61
275 ± 76
(min 221, max 391)
(min 143, max 391)
(min 150, max 435)
median 282
median 232
median 268
5209 ± 3504
2455 ± 1401
2711 ± 2204
(min 1020, max 10489)
(min 673, max 8231)
(min 424, max 11087)
median 4828
median 2062
median 2286
Number of transfusion
Ferritin (mg/dl) (mean ± SD)
60.4 ± 12.5
75.5 ± 6.9
72.5 ± 4.4
(min 41, max 73) median 60
(min 60, max 89) median 78
(min 63, max 80) median 70
Yes
4
16
11
No
1
18
14
LVEF (%) (mean ± SD)
NS
NS
NS
0.006
Splenectomy NS
LVEF left ventricular ejection fraction, MRI magnetic resonance imaging, NS not significant
Following the assessment of the patients with T2* MRI in terms of their cardiac risks, chelation therapies of 24 patients (37.5 %) were rearranged with consents of their families. Transition from monotherapy (DFO:8, DFX:1) to combination therapy was carried out in nine patients. While the T2* MRI levels of 2 of these patients were \10 ms, they ranged between 10 and 20 ms in 7 patients. Transition from the DFO therapy to the DFX therapy was carried out in 8 patients; 5 of them were medium risk, and the other 3 were low risk according to the T2* MRI evaluation. T2* MRI was between 10 and 20 ms in two of the 6 patients, who were transitioned from combination therapy to DFX therapy and it was [ 20 ms in 4 patients. Transition from the DFO therapy to the DFP therapy was carried out in one patient with T2* MRI value between 10 and 20 ms. After this changes, DFO ? DFP therapy was introduced to 36 patients, DFX therapy was given to 20 patients, DFO therapy was given to 7 patients and 1 patient had DFP monotherapy. While there was a decrease in the number of the patients receiving DFO monotherapy with this adjustment, the number of patients using DFX and DFO ? DFP combination therapy had increased (Fig. 4).
The distribution of chelation therapies before and after T2* MRI are depicted in Table 3 and general characteristics of the patients with therapy modifications made after T2* MRI had been summarized in web Table 1. In addition, 11 of our patients, for whom combination therapy was not obligatory since their T2* MRI values were [20 ms, continued with this therapy because they were used to it. One patient with T2* MRI value of 7.5 ms died due to heart failure.
Discussion While patients with TM were died during the first decade of their lives before regular transfusion and chelation therapies, various groups from different countries reported that the life expectancy in these patients displayed a gradual increase [12, 13]. An efficient iron chelation therapy leading to prevention of various organ dysfunctions and cardiac deaths plays a major role in this achievement [12–14]. Thus, T2* MRI has become a reliable method that provides guidance to haematologists in identifying the
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Fig. 1 The relationship between T2* MRI and serum ferritin levels. The median serum ferritin level of the patients within the group, whose T2* MRI values were \10 ms, was higher compared to those of the other groups. However, this difference was not statistically significant (P = 0.057). Each box shows the median, quartiles, and extreme values within the category
A. Akcay et al.
Fig. 3 The relationship between T2* MRI and ages of patients. The median age of the patients within the group, whose T2* MRI values were \10 ms, was older compared to those of the other groups. However, this difference of age was not statistically significant (P = 0.509). Each box shows the median, quartiles, and extreme values within the category
Fig. 4 The distribution of chelation therapies received by the patients before and after T2* MRI. DFO deferoxamine, DFP deferiprone, DFX deferasirox Fig. 2 The relationship between T2* MRI and left ventricular ejection fraction (LVEF). The median LVEF of the patients within the group, whose T2* MRI values were\10 ms, was lower compared to those of the other groups and there were significant differences among all groups (P = 0.006). In the examination between binary groups (for the groups with T2* \ 10 ms and between 10 and 20 ms, P = 0.007; for the groups with \10 ms and [20 ms, P = 0.026; for the groups with 10 and 20 and [20 ms, P = 0.044). Each box shows the median, quartiles, and extreme values within the category
cardiac risk at an early stage and introduced a new perspective in directing chelation therapies. But modifications of chelation therapies that were tailored according to T2* MRI results were less frequently mentioned in the literature. In the various studies, parameters used during followup of these patients at hematology clinics were compared
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with the values obtained by T2* MRI. Cardiac T2* MRI values with respect to alternative chelation therapies had been also studied [15–18]. Even though the cardiac iron accumulation starts in the second decade of life in TM cases, there is no linear relationship between the age and the cardiac iron. This situation gives rise to considerations that not only the duration of transfusion but also the duration of and adherence to chelation therapy are the determinants of cardiac iron accumulation [4, 19]. Although at a crosssectional study, it was shown that there was no correlation between cardiac T2* and serum ferritin concentrations in patients receiving iron chelation therapy [20], at longitudinal studies, a significant relationship between these
Cardiac T2* MRI and choice of chelation therapy
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Table 3 The distribution of chelation therapies received by the patients before T2* magnetic resonance imaging and the modifications according to T2* magnetic resonance imaging T2* MRI
Chelation therapy DFO ? DFP Before T2*
\10 ms
DFO After T2*
Before T2*
DFX After T2*
Before T2*
DFP After T2*
Before T2*
After T2*
3
5
1
–
1
–
–
–
10–20 ms
15
20
18
5
1
8
–
1
[20 ms
15
11
5
2
5
12
–
–
DFO deferoxamine, DFP deferiprone, DFX deferasirox, MRI magnetic resonance imaging
variables were presented [6, 21]. While statistically not significant, our high-risk group (n 5 patients) was older and their serum ferritin levels were higher compared to the other two groups. The statistical insignificance might be attributed to the low number of patients within this group. The LVEF level was lower in the high-risk group compared to the other groups and there was a statistically significant difference among all groups. Even though, we could not show a relationship between T2* MRI levels and the other variables, studies with larger number of patients may help to point out this relationship. When we compared the high risk and the medium-risk group, we determined that their ages were older, their serum ferritin values were higher, and LVEF was lower. However, this linear relationship did not exist between the medium-risk group and the low-risk group. LVEF values were higher in the medium-risk group than the low-risk group (median LVEF 75.5 % ± 6.9 and 72.5 % ± 4.4, P = 0.044). Although this may be explained by an early compensatory mechanism of cardiac failure in medium-risk group, we know that subtle changes of the position and axis of the echo probe may affect the calculated LVEF even the same physician had performed the echocardiography. So, the statistically significant difference may not have a clinical importance and may occur coincidentally. The ratio of the patients with splenectomy was higher among the high-risk group (four of five patients). However, no relationship was determined between the splenectomy condition and T2* MRI, either. The non-existence of a statistical relationship may be due to the low number of our patients with severe cardiac iron accumulation. In the study conducted by Aydınok et al. [22] on 146 TM cases, myocardial siderosis (T2* MRI \20 ms) was determined as 48 % in cases with splenectomy and 28 % in those without splenectomy and attention was drawn to the role of the spleen in iron regulation. There are many guides used throughout the world while directing the iron chelation therapy in TM patients [11, 23, 24]. These guides have recommended therapies according to such parameters as the ferritin level, total iron load of the body, LVEF, and liver iron load until recently. T2* MRI
was also included in chelation guides upon the start of its use in determining the cardiac iron load of patients. The recommendations included in the guide of the United Kingdom Thalassaemia Society are taken as basis for the following of TM patients and the determination of their chelation therapies at our centre. Chelation therapies of 24 patients (37.5 %) were rearranged following T2* MRI. The most frequent change of drugs according to the results of T2* MRI assessments was observed to take place as a transition from DFO or DFO ? DFP combination therapy to DFX (n = 14). While the number of patients using the DFO monotherapy decreased with these arrangements, the number of those using the DFX and DFO ? DFP increased. Intensive combined chelation regimens are required for removing the iron rapidly in patients with T2* MRI values below 10 ms. Combined chelation regimens (DFO ? DFP) that would remove the cardiac iron rapidly are recommended to be applied in the patients determined to have severe cardiac iron accumulation with the T2* MRI assessment [11]. A synergistic impact takes place with the combined use of DFO and DFP [25]. With the prevalent use of DFX, which is a newer oral chelating agent, studies indicating that DFX decreased myocardial iron accumulation were published as well [26, 27]. It was also shown that DFX also reduced myocardial iron accumulation and ensured a continuous improvement in T2* MRI values as the duration of its use extends and that it could be safely used. A significant increase was determined in T2* MRI values as a result of the use of DFX for a period of 3 years in the EPIC study conducted on 71 patients and this study was published in 2012 [28]. Chelation therapies of the patients with T2*MRI values between 10 and 20 ms should be examined carefully without any regard to the drug used by them (DFO, DFO ? DFP, DFX). It was reported in the EPIC study that T2* MRI reached normal levels ([20 ms) with the DFX therapy in 68 % of the 47 patients, whose initial T2* values were between 10 and 20 ms [28]. While the DFO ? DFP combination therapy was used in 20 of these patients, the monotherapy of DFX was used in 8, DFO was used in 5, and DFP was used in one patient. When the first T2* MRIs
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were performed to our patients, results of the studies with respect to long term cardiac effects of DFX had not been published. For this reason, DFO ? DFP combination therapy was preferred in the group with T2* MRI 10–20 ms. DFX is recommended for chelation in patients with T2* MRI values higher than 20 ms [17, 29]. However, improvements had been reported in cardiac T2* MRI values by the use of DFO, DFP monotherapies and also DFO and DFP combined therapy at low-risk group [16, 30]. It is recommended that patients undergo cardiac MRI T2* measurement at least yearly if they have abnormal values (\20 ms) or more frequently if with diagnosed heart disease; and once every 2 years in those with values [20 ms and normal cardiac function. Owing to the risk of cardiac decompensation, patients with T2* MRI \10 ms should be evaluated twice a year and if they had heart failure, at every 3 months [31]. The most frequent change of drugs according to the results of T2* MRI assessments was observed to take place as a transition from DFO or DFO ? DFP combination therapy to DFX. The intensity of the therapy was reduced safely and monodose therapy could be applied to our patients with T2* MRI values above 20 ms that were receiving combination therapy before the imaging.
Conclusion The team directing the thalassaemia therapy will be able to choose alternative therapies according to T2* MRI results and this in turn will result in improvements in the prognosis of TM patients. The weakness of this study is the low number of patient’s enrolled; larger series will increase the strength of our assumption. There are a few studies in literature regarding to modifications in chelation therapies according to T2* MRI results In this respect, we emphasize the requirement of the transition to more concentrated therapies in cases with T2* MRI values below 10 ms. It should be kept in mind that the safe shifting from intensive therapy to monotherapy might become possible by evaluating T2* MRI results. This ensures both sufficient chelation, improvement in quality of life, and adherence to therapy with less side effects. Conflict of interest
None stated.
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